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Abstract:

The present invention is directed to novel processes for the preparation
of histamine H3 receptor modulators, in the treatment of for example,
cognitive disorders, sleep disorders and/or psychiatric disorders.
##STR00001##

Claims:

1. A process for the preparation of a compound of formula (I)
##STR00059## wherein R1 is selected from the group consisting of
C1-4alkyl and C3-10cycloalkyl; m is an integer from 1 to 2;
R2 is selected from the group consisting of --OCHR3R4 and
--Z--Ar; R3 is hydrogen and R4 is a C3-10cycloalkyl or
heterocycloalkyl ring; wherein the C3-10cycloalkyl or the
heterocycloalkyl ring is unsubstituted or substituted with
--C1-4alkyl or acetyl; alternatively, R3 and R4 are taken
together with the carbon to which they are attached to form a
C3-10cycloalkyl or heterocycloalkyl ring; wherein the
C3-10cycloalkyl or the heterocycloalkyl ring is unsubstituted or
substituted with --C1-4alkyl or acetyl; Z is selected from the group
consisting of S and O; Ar is a phenyl or heteroaryl; wherein the phenyl
or heteroaryl is unsubstituted or substituted with one, two, or three
R5 substituents; wherein each R5 substituent is independently
selected from the group consisting of halogen, --C1-4alkyl, --OH,
--OC1-4alkyl, --SC1-4alkyl, --CN, --CONRaRb, and
--NO2; and wherein Ra and Rb are each independently --H or
--C1-4alkyl; or a pharmaceutically acceptable salt, a
pharmaceutically acceptable prodrug, or a pharmaceutically active
metabolite thereof; comprising ##STR00060## reacting a compound of
formula (V) with a compound of formula (VI), wherein LG1 is a first
leaving group and LG2 is a second leaving group, in the presence of
a base, in an organic solvent; to yield the corresponding compound of
formula (VII); ##STR00061## reacting the compound of formula (VII) with
an aldehyde or ketone derivative of the desired R1 substituent
group; in the presence of a reducing agent; in an organic solvent; to
yield the corresponding compound of formula (X); ##STR00062## reacting
the compound of formula (X) with a compound of formula (XII); in the
presence of a first inorganic base; in an organic solvent; or reacting
the compound of formula (X) with a compound of formula (XIII); in the
presence of a second inorganic base; in an organic solvent; to yield the
corresponding compound of formula (I).

2. A process as in claim 1, wherein R1 is cyclobutyl, m is 1 and
R2 is selected from the group consisting of 4-fluorophenyl,
3-cyanophenyl, 4-tetrahydropyranyl, LG1 is chloro and LG2 is
chloro.

3. A process for the preparation of a compound of formula (I-E)
##STR00063## wherein R1 is selected from the group consisting of
C1-4alkyl and C3-10cycloalkyl; m is 2 R2 is selected from
the group consisting of --OCHR3R4 and --Z--Ar; R3 is
hydrogen and R4 is a C3-10cycloalkyl or heterocycloalkyl ring;
wherein the C3-10cycloalkyl or the heterocycloalkyl ring is
unsubstituted or substituted with --C1-4alkyl or acetyl;
alternatively, R3 and R4 are taken together with the carbon to
which they are attached to form a C3-10cycloalkyl or
heterocycloalkyl ring; wherein the C3-10cycloalkyl or the
heterocycloalkyl ring is unsubstituted or substituted with
--C1-4alkyl or acetyl; Z is selected from the group consisting of S
and O; Ar is a phenyl or heteroaryl; wherein the phenyl or heteroaryl is
unsubstituted or substituted with one, two, or three R5
substituents; wherein each R5 substituent is independently selected
from the group consisting of halogen, --C1-4alkyl, --OH, --CN,
--CONRaRb, and --NO2; and wherein Ra and Rb are
each independently --H or --C1-4alkyl; or a pharmaceutically
acceptable salt, a pharmaceutically acceptable prodrug, or a
pharmaceutically active metabolite thereof; comprising ##STR00064##
reacting a compound of formula (V-S) with an aldehyde or ketone
derivative of the desired R1 substituent group; neat or in an
organic solvent; to yield the corresponding compound of formula (IX);
##STR00065## reacting the compound of formula (IX) with a reducing
agent; neat, in water or in an aqueous organic solvent; to yield the
corresponding compound of formula (XI); ##STR00066## reacting the
compound of formula (XI) with a compound of formula (VI), wherein
LG1 is a first leaving group and LG2 is a second leaving group;
in an organic solvent; alternatively reacting the compound of formula
(XI) with a compound of formula (VI) wherein LG1 is a first leaving
group and LG2 is a second leaving group; in the presence of a base;
in a mixture of water and an organic solvent; to yield the corresponding
compound of formula (X-E) ##STR00067## reacting the compound of formula
(X-E) with a compound of formula (XII); in the presence of a first
inorganic base; in an organic solvent; or reacting the compound of
formula (X-E) with a compound of formula (XIII); in the presence of a
second inorganic base; in an organic solvent; to yield the corresponding
compound of formula (I-E).

4. A process as in claim 3, wherein R1 is cyclobutyl, m is 1 and
R2 is selected from the group consisting of 4-fluorophenyl,
3-cyanophenyl, 4-tetrahydropyranyl, LG1 is chloro and LG2 is
chloro.

5. A process for the preparation of a compound of formula (I-E)
##STR00068## wherein R1 is selected from the group consisting of
C1-4alkyl and C3-10cycloalkyl; m is 2 R2 is selected from
the group consisting of --OCHR3R4 and --Z--Ar; R3 is
hydrogen and R4 is a C3-10cycloalkyl or heterocycloalkyl ring;
wherein the C3-10cycloalkyl or the heterocycloalkyl ring is
unsubstituted or substituted with --C1-4alkyl or acetyl;
alternatively, R3 and R4 are taken together with the carbon to
which they are attached to form a C3-10cycloalkyl or
heterocycloalkyl ring; wherein the C3-10cycloalkyl or the
heterocycloalkyl ring is unsubstituted or substituted with
--C1-4alkyl or acetyl; Z is selected from the group consisting of S
and O; Ar is a phenyl or heteroaryl; wherein the phenyl or heteroaryl is
unsubstituted or substituted with one, two, or three R5
substituents; wherein each R5 substituent is independently selected
from the group consisting of halogen, --C1-4alkyl, --OH,
--OC1-4alkyl, --SC1-4alkyl, --CN, --CONRaRb, and
--NO2; and wherein Ra and Rb are each independently --H or
--C1-4alkyl; or a pharmaceutically acceptable salt, a
pharmaceutically acceptable prodrug, or a pharmaceutically active
metabolite thereof; comprising ##STR00069## reacting a compound of
formula (V-S) with an aldehyde or ketone derivative of the desired
R1 substituent group; neat or in an organic solvent; to yield the
corresponding compound of formula (IX); ##STR00070## reacting the
compound of formula (IX) with a compound of formula (VI), wherein
LG1 is a first leaving group and LG2 is a leaving group; in the
presence of a reducing agent; in an organic solvent; to yield the
corresponding compound of formula (X-E) ##STR00071## reacting the
compound of formula (X-E) with a compound of formula (XII); in the
presence of a first inorganic base; in an organic solvent; or reacting
the compound of formula (X-E) with a compound of formula (XIII); in the
presence of a second inorganic base; in an organic solvent; to yield the
corresponding compound of formula (I-E).

6. A process as in claim 5, wherein R1 is cyclobutyl, m is 1 and
R2 is selected from the group consisting of 4-fluorophenyl,
3-cyanophenyl, 4-tetrahydropyranyl, LG1 is chloro and LG2 is
chloro.

7. A process for the preparation of compound (I-C) ##STR00072## or a
pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug,
or a pharmaceutically active metabolite thereof; comprising ##STR00073##
reacting a compound of formula (V-S) with a compound of formula
(VIII-S), neat or in an organic solvent; to yield the corresponding
compound of formula (IX-S); ##STR00074## reacting the compound of
formula (IX-S) with a reducing agent; neat, in water or in an organic
solvent; to yield the corresponding compound of formula (XI-S);
##STR00075## reacting the compound of formula (XI-S) with a compound of
formula (VI-S), wherein LG1 is a first leaving group and LG2 is
a second leaving group; in an organic solvent; alternatively, reacting
the compound of formula (XI-S) with a compound of formula (VI-S), wherein
LG1 is a first leaving group and LG2 is a second leaving group;
in the presence of a base; in a mixture of water and an organic solvent;
to yield the corresponding compound of formula (X-S); ##STR00076##
reacting the compound of formula (X-S) with a compound of formula
(XII-C); in the presence of a second inorganic base; in an organic
solvent; to yield the corresponding compound (I-C).

8. A process as in claim 7, wherein the compound of formula (VIII-S) is
present in an amount in the range of from about 1.0 to about 1.5 molar
equivalents.

9. A process as in claim 8, wherein the compound of formula (VIII-S) is
present in an amount of about 1.05 molar equivalents.

10. A process as in claim 7, wherein the compound of formula (V-S) is
reacted with the compound of formula (VIII-S) in an organic solvent and
wherein the organic solvent is toluene.

11. A process as in claim 7, wherein the compound of formula (V-S) is
reacted with the compound of formula (VIII-S) at a temperature of about
reflux temperature.

12. A process as in claim 7, wherein the compound of formula (IX-S) is
reacted with the reducing agent in the presence of an acid.

13. A process as in claim 12, wherein the acid is hydrochloric acid and
is present in an amount in the range of from about 3.0 to about 5.0 molar
equivalents.

14. A process as in claim 7, wherein the reducing agent is added as a
solution in water, stabilized with sodium hydroxide in an amount of about
0.1 molar equivalents.

15. A process as in claim 7, wherein the reducing agent is sodium
borohydride.

16. A process as in claim 15, wherein the sodium borohydride is present
in an amount in the range of from about 0.5 to about 1.5 molar
equivalents.

17. A process as in claim 7, wherein the compound of formula (IX-S) is
reacted with the reducing agent at a temperature in the range of from
about -10.degree. C. to about 0.degree. C.

18. A process as in claim 7, wherein the compound of formula (VI-S)
LG1 and LG2 are each chloro.

19. A process as in claim 7, wherein the compound of formula (VI-S) is
present in an amount in the range of from about 1.0 to abut 1.5 molar
equivalents.

20. A process as in claim 19, wherein the compound of formula (VI-S) is
present in an amount of about 1.05 molar equivalents.

21. A process as in claim 7, wherein the compound of formula (XI-S) is
reacted with the compound of formula (VI-S) in an organic solvent
selected from the group consisting of methyl t-butyl ether, toluene and
2-methyl-THF.

22. A process as in claim 7, wherein the compound of formula (XI-S) is
reacted with the compound of formula (VI-S) at a temperature in the range
of from about 0.degree. C. to about 35.degree. C.

23. A process as in claim 7, wherein the compound of formula (XI-S) is
reacted with the compound of formula (VI-S) in the presence of a base;
wherein the base is sodium hydroxide; and wherein the sodium hydroxide is
present in an amount in the range of form about 1.05 to about 1.2 molar
equivalents.

24. A process as in claim 7, wherein the compound of formula (VI-S) in
MTBE is reacted with the compound of formula (XI-S) in water, in the
presence of 30% NaOH, at a temperature in the range of from about
10.degree. C. to about 15.degree. C.

25. A process as in claim 7, wherein the compound of formula (XII-C) is
present in an amount in the range of from about 1.1 to about 1.5 molar
equivalents.

26. A process as in claim 7, wherein the second inorganic base is
potassium hydroxide.

27. A process as in claim 26, wherein the potassium hydroxide is present
in an amount in the range of from about 2.0 to about 4.0 molar
equivalents.

28. A process as in claim 7, wherein the compound of formula (X-S) is
reacted with the compound of formula (XII-A) in an organic solvent
selected from the group consisting of toluene, acetonitrile and a mixture
of toluene and water.

29. A process as in claim 7, wherein the compound of formula (X-S) is
reacted with the compound of formula (XII-C) at about reflux temperature.

30. A process as in claim 7, wherein LG2 is chloro and wherein the
compound of formula (X-S) is prepared as its corresponding HCl salt.

31. A process as in claim 30, wherein the compound of formula (X-S) as
its corresponding HCl salt is reacted with a first inorganic base prior
to reacting with compound of formula (XII-C).

32. A process as in claim 31, wherein the first inorganic base is sodium
carbonate.

33. A process as in claim 32, wherein the sodium carbonate is present in
an amount sufficient to liberate the compound of formula (X-S) as a free
base.

34. A process as in claim 32, wherein the sodium carbonate is present in
an amount of about 1.5 molar equivalents.

35. A process for the preparation of a compound of formula (X-S)
##STR00077## wherein LG1 is a first leaving group; comprising
##STR00078## reacting a compound of formula (V-S) with a compound of
formula (VIII-S), neat or in an organic solvent; to yield the
corresponding compound of formula (IX-S); ##STR00079## reacting the
compound of formula (IX-S) with a reducing agent; neat, in water or in an
organic solvent; to yield the corresponding compound of formula (XI-S);
##STR00080## reacting the compound of formula (XI-S) with a compound of
formula (VI-S), wherein LG2 is a second leaving group; in an organic
solvent; alternatively reacting the compound of formula (XI-S) with a
compound of formula (VI-S), wherein LG2 is a second leaving group;
in the presence of a base; in a mixture of water and an organic solvent;
to yield the corresponding compound of formula (X-S).

36. A process as in claim 35, wherein LG1 is chloro.

37. A process as in claim 35, wherein the compound of formula (VIII-S) is
present in an amount in the range of from about 1.0 to about 1.5 molar
equivalents.

38. A process as in claim 35, wherein the compound of formula (V-S) is
reacted with the compound of formula (VIII-S) in toluene, at a
temperature greater than about 40.degree. C.

39. A process as in claim 35, wherein the compound of formula (IX-S) is
reacted with the reducing agent in the presence an acid; wherein the acid
is hydrochloric acid; and wherein the hydrochloric acid is present in an
amount in the range of from about 3.0 to about 5.0 molar equivalents.

40. A process as in claim 35, wherein the reducing agent is sodium
borohydride and wherein the reducing agent is added as a solution in
water, stabilized with about 0.1 molar equivalents of sodium hydroxide.

41. A process as in claim 35, wherein the compound of formula (IX-S) is
reacted at a temperature in the range of from about -10.degree. C. to
about 0.degree. C.

42. A process as in claim 35, wherein LG2 is chloro; wherein the
compound of formula (VI-S) is present in an amount in the range of from
about 1.0 to about 1.5 molar equivalents; and wherein the compound of
formula (X-S) is prepared as its corresponding HCl salt.

43. A process as in claim 35, wherein the compound of formula (XI-S) is
reacted with the compound of formula (VI-S) in an organic solvent
selected from the group consisting of toluene and 2-methyl-THF; and at a
temperature in the range of form about room temperature to about
35.degree. C.

44. A process as in claim 35, wherein the compound of formula (XI-S) in
water is reacted with a compound of formula (VI-S) in MTBE, in the
presence of a base; wherein the base is 30% NaOH; at a temperature in the
range of from about 10.degree. C. to about 15.degree. C.

47. A process for the preparation of the crystalline form of the HCl salt
of compound (I-C) as in claim 46, comprising reacting compound (I-C) with
anhydrous HCl acid in isopropanol.

Description:

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application
61/161/177, filed on Mar. 18, 2009.

FIELD OF THE INVENTION

[0002] The present invention is directed to novel processes for the
preparation of histamine H3 receptor modulators, in the treatment of for
example, cognitive disorders, sleep disorders and/or psychiatric
disorders.

BACKGROUND OF THE INVENTION

[0003] The histamine H3 receptor was first described as a presynaptic
autoreceptor in the central nervous system (CNS) (ARRANG, J.-M. et al.,
"Auto-inhibition of brain histamine release mediated by a novel class
(H3) of histamine receptor", Nature, 1983, pp 832-837, vol. 302)
controlling the synthesis and release of histamine. The histamine H3
receptor is primarily expressed in the mammalian central nervous system
(CNS), with some minimal expression in peripheral tissues such as
vascular smooth muscle.

[0006] Keith, J. M. et al., in US Patent Publication 2007/0281923-A1,
published Dec. 6, 2007 disclose pyridyl amide compounds, methods of
making them, pharmaceutical compositions containing them, and methods of
using them for the treatment of disease states, disorders, and conditions
mediated by the histamine H3 receptor.

[0007] Letavic, M., et al., in U.S. Patent Publication 2009/0131415 A1,
published May 17, 2009 disclose cycloalkyloxy- and
heterocycloalkyloxypyridine compounds, methods of making them,
pharmaceutical compositions containing them, and methods of using them
for the treatment of disease states, disorders, and conditions mediated
by the histamine H3 receptor.

SUMMARY OF THE INVENTION

[0008] The present invention is directed to processes for the preparation
of compounds of formula (I)

##STR00002##

[0009] wherein

[0010] R1 is selected from the group consisting of C1-4alkyl and
C3-10cycloalkyl;

[0011] m is an integer from 1 to 2;

[0012] R2 is selected from the group consisting of
--OCHR3R4 and --Z--Ar;

[0013] R3 is hydrogen and R4 is a C3-10cycloalkyl or
heterocycloalkyl ring; wherein the C3-10cycloalkyl or the
heterocycloalkyl ring is unsubstituted or substituted with
--C1-4alkyl or acetyl;

[0014] alternatively, R3 and R4 are taken together with the
carbon to which they are attached to form a C3-10cycloalkyl or
heterocycloalkyl ring; wherein the C3-10cycloalkyl or the
heterocycloalkyl ring is unsubstituted or substituted with
--C1-4alkyl or acetyl;

[0015] Z is selected from the group consisting of S and O;

[0016] Ar is a phenyl or heteroaryl; wherein the phenyl or heteroaryl is
unsubstituted or substituted with one, two, or three R5
substituents; wherein each R5 substituent is independently selected
from the group consisting of halogen, --C1-4alkyl, --OH,
--OC1-4alkyl, --SC1-4alkyl, --CN, --CONRaRb, and
--NO2; and wherein Ra and Rb are each independently --H or
--C1-4alkyl;

[0018] reacting a compound of formula (V) with a compound of formula (VI),
wherein LG1 is a first leaving group and LG2 is a second
leaving group, in the presence of a base, in an organic solvent; to yield
the corresponding compound of formula (VII);

##STR00004##

[0019] reacting the compound of formula (VII) with an aldehyde or ketone
derivative of the desired R1 substituent group; in the presence of a
reducing agent; in an organic solvent; to yield the corresponding
compound of formula (X);

##STR00005##

[0020] reacting the compound of formula (X) with a compound of formula
(XII); in the presence of a first inorganic base; in an organic solvent;
or

[0021] reacting the compound of formula (X) with a compound of formula
(XIII); in the presence of a second inorganic base; in an organic
solvent;

[0022] to yield the corresponding compound of formula (I).

[0023] The present invention is directed to processes for the preparation
of compounds of formula (I-E)

##STR00006##

[0024] wherein

[0025] R1 is selected from the group consisting of C1-4alkyl and
C3-10cycloalkyl;

[0026] m is 2

[0027] R2 is selected from the group consisting of
--OCHR3R4 and --Z--Ar;

[0028] R3 is hydrogen and R4 is a C3-10cycloalkyl or
heterocycloalkyl ring; wherein the C3-10cycloalkyl or the
heterocycloalkyl ring is unsubstituted or substituted with
--C1-4alkyl or acetyl;

[0029] alternatively, R3 and R4 are taken together with the
carbon to which they are attached to form a C3-10cycloalkyl or
heterocycloalkyl ring; wherein the C3-10cycloalkyl or the
heterocycloalkyl ring is unsubstituted or substituted with
--C1-4alkyl or acetyl;

[0030] Z is selected from the group consisting of S and O;

[0031] Ar is a phenyl or heteroaryl; wherein the phenyl or heteroaryl is
unsubstituted or substituted with one, two, or three R5
substituents; wherein each R5 substituent is independently selected
from the group consisting of halogen, --C1-4alkyl, --OH,
--OC1-4alkyl, --SC1-4alkyl, --CN, --CONRaRb, and
--NO2; and wherein Ra and Rb are each independently --H or
--C1-4alkyl;

[0033] reacting a compound of formula (V-S) with an aldehyde or ketone
derivative of the desired R1 substituent group; neat or in an
organic solvent; to yield the corresponding compound of formula (IX);

##STR00008##

[0034] reacting the compound of formula (IX) with a reducing agent; neat,
in water or an aqueous organic solvent; to yield the corresponding
compound of formula (XI);

##STR00009##

[0035] reacting the compound of formula (XI) with a compound of formula
(VI), wherein LG1 is a first leaving group and LG2 is a second
leaving group; in an organic solvent;

[0036] alternatively reacting the compound of formula (XI) with a compound
of formula (VI), wherein LG1 is a first leaving group and LG2
is a second leaving group; in the presence of a base; in a mixture of
water and an organic solvent;

[0037] solvent or mixture of solvents;

[0038] to yield the corresponding compound of formula (X-E)

##STR00010##

reacting the compound of formula (X-E) with a compound of formula (XII);
in the presence of a first inorganic base; in an organic solvent; or

[0039] reacting the compound of formula (X-E) with a compound of formula
(XIII); in the presence of a second inorganic base; in an organic
solvent;

[0040] to yield the corresponding compound of formula (I-E).

[0041] The present invention is directed to processes for the preparation
of compounds of formula (I-E)

##STR00011##

[0042] wherein

[0043] R1 is selected from the group consisting of C1-4alkyl and
C3-10cycloalkyl;

[0044] m is 2

[0045] R2 is selected from the group consisting of
--OCHR3R4 and --Z--Ar;

[0046] R3 is hydrogen and R4 is a C3-10cycloalkyl or
heterocycloalkyl ring; wherein the C3-10cycloalkyl or the
heterocycloalkyl ring is unsubstituted or substituted with
--C1-4alkyl or acetyl;

[0047] alternatively, R3 and R4 are taken together with the
carbon to which they are attached to form a C3-10cycloalkyl or
heterocycloalkyl ring; wherein the C3-10cycloalkyl or the
heterocycloalkyl ring is unsubstituted or substituted with
--C1-4alkyl or acetyl;

[0048] Z is selected from the group consisting of S and O;

[0049] Ar is a phenyl or heteroaryl; wherein the phenyl or heteroaryl is
unsubstituted or substituted with one, two, or three R5
substituents; wherein each R5 substituent is independently selected
from the group consisting of halogen, --C1-4alkyl, --OH,
--OC1-4alkyl, --SC1-4alkyl, --CN, --CONRaRb, and
--NO2; and wherein Ra and Rb are each independently --H or
--C1-4alkyl;

[0051] reacting a compound of formula (V-S) with an aldehyde or ketone
derivative of the desired R1 substituent group; neat or in an
organic solvent; to yield the corresponding compound of formula (IX);

##STR00013##

[0052] reacting the compound of formula (IX) with a compound of formula
(VI), wherein LG1 is a first leaving group and LG2 is a second
leaving group; in the presence of a reducing agent; in an organic
solvent; to yield the corresponding compound of formula (X-E)

##STR00014##

[0053] reacting the compound of formula (X-E) with a compound of formula
(XII); in the presence of a first inorganic base; in an organic solvent;
or

[0054] reacting the compound of formula (X-E) with a compound of formula
(XIII); in the presence of a second inorganic base; in an organic
solvent;

[0055] to yield the corresponding compound of formula (I-E).

[0056] In an embodiment, the present invention is directed to processes
for the preparation of compound (I-A)

##STR00015##

[0057] or a pharmaceutically acceptable salt, a pharmaceutically
acceptable prodrug, or a pharmaceutically active metabolite thereof; also
known as (4-cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin--
3-yl]-methanone; as described in more detail herein.

[0058] In another embodiment, the present invention is directed to a
process for the preparation of compound (I-B)

##STR00016##

[0059] or a pharmaceutically acceptable salt, a pharmaceutically
acceptable prodrug, or a pharmaceutically active metabolite thereof; also
known as 3-[5-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-pyridin-2-yloxy]-b-
enzonitrile; as described in more detail herein.

[0060] In another embodiment, the present invention is directed to a
process for the preparation of compound (I-C)

##STR00017##

[0061] or a pharmaceutically acceptable salt, a pharmaceutically
acceptable prodrug, or a pharmaceutically active metabolite thereof; also
known as (4-cyclobutyl-[1,4]diazepan-1-yl)-[6-(tetrahydro-pyran-4-yloxy)--
pyridin-3-yl]-methanone; as described in more detail herein.

[0062] The present invention is directed to processes for the preparation
of compounds of formula (X)

##STR00018##

[0063] wherein

[0064] R1 is selected from the group consisting of C1-4alkyl and
C3-10cycloalkyl;

[0065] m is an integer from 1 to 2;

[0066] LG1 is a first leaving group;

[0067] or a pharmaceutically acceptable salt, thereof; comprising

##STR00019##

[0068] reacting a compound of formula (V) with a compound of formula (VI),
wherein LG2 is a second leaving group, in the presence of a base, in
an organic solvent; to yield the corresponding compound of formula (VII);

##STR00020##

[0069] reacting the compound of formula (VII) with an aldehyde or ketone
derivative of the desired R1 substituent group; in the presence of a
reducing agent; in an organic solvent; to yield the corresponding
compound of formula (X).

[0070] The present invention is further directed to a process for the
preparation of compounds of formula (X-E)

##STR00021##

[0071] wherein

[0072] R1 is selected from the group consisting of C1-4alkyl and
C3-10cycloalkyl;

[0073] m is 2;

[0074] LG1 is a first leaving group;

[0075] or a pharmaceutically acceptable salt, thereof; comprising

##STR00022##

[0076] reacting a compound of formula (V-S) with an aldehyde or ketone
derivative of the desired R1 substituent group; neat or in an
organic solvent; to yield the corresponding compound of formula (IX);

##STR00023##

[0077] reacting the compound of formula (IX) with a reducing agent; neat,
in water or an aqueous organic solvent; to yield the corresponding
compound of formula (XI);

##STR00024##

[0078] reacting the compound of formula (XI) with a compound of formula
(VI), wherein LG2 is a second leaving group; in an organic solvent;

[0079] alternatively reacting the compound of formula (XI) with a compound
of formula (VI), wherein LG1 is a first leaving group and LG2
is a second leaving group; in the presence of a base; in a mixture of
water and an organic solvent;

[0080] to yield the corresponding compound of formula (X-E).

[0081] The present invention is further directed to a process for the
preparation of compounds of formula (X-E)

##STR00025##

[0082] wherein

[0083] R1 is selected from the group consisting of C1-4alkyl and
C3-10cycloalkyl;

[0084] m is 2;

[0085] LG1 is a first leaving group;

[0086] or a pharmaceutically acceptable salt, thereof; comprising

##STR00026##

[0087] reacting a compound of formula (V-S) with an aldehyde or ketone
derivative of the desired R1 substituent group; neat or in an
organic solvent; to yield the corresponding compound of formula (IX);

##STR00027##

[0088] reacting the compound of formula (IX) with a compound of formula
(VI), wherein LG2 is a second leaving group; in the presence of a
reducing agent; in an organic solvent; to yield the corresponding
compound of formula (X-E).

[0089] In an embodiment, the present invention is directed to processes
for the preparation of compounds of formula (X-S)

##STR00028##

[0090] wherein LG1 is a first leaving group; or pharmaceutically
acceptable salt thereof; as described in more detail herein. The present
invention is further directed to a process for the purification of the
compound of formula (X-S), as described in more detail herein.

[0091] The present invention is further directed to two novel crystalline
HCl salts of compound (I-B), as described in more detail hereinafter, and
as referred to as FORM I and FORM II. The present invention is further
directed to processes for the preparation of the crystalline HCl salts of
compound (I-B).

[0092] The present invention is further directed to a novel crystalline
HCl salt of compound (I-C), as described in more detail hereinafter. The
present invention is further directed to a process for the preparation of
the crystalline HCl salt of compound (I-C).

[0093] The present invention is further directed to a product prepared
according to any of the processes described herein.

[0094] Illustrative of the invention is a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and any compound,
crystalline salt or product as described herein. An illustration of the
invention is a pharmaceutical composition made by mixing any compound,
crystalline salt or product as described herein and a pharmaceutically
acceptable carrier. Illustrating the invention is a process for making a
pharmaceutical composition comprising mixing any compound, crystalline
salt or product as described herein and a pharmaceutically acceptable
carrier.

[0095] In another general aspect, the present invention is directed to
methods for treating a subject suffering from or diagnosed with a
disease, disorder, or medical condition mediated by histamine H3
receptor activity, comprising administering to a subject in need of such
treatment an effective amount of any compound, crystalline salt or
product as described herein. In certain preferred embodiments of the
present invention, the disease, disorder, or medical condition is
selected from the group consisting of cognitive disorders, sleep
disorders, psychiatric disorders, and other disorders.

[0096] In another aspect, the present invention is directed to the use of
any compound, crystalline salt or product as described herein for the
preparation of a medicament for the treatment of a disease, disorder, or
medical condition mediated by histamine H3 receptor activity,
including (a) cognitive disorders, (b) sleep disorders, (c) psychiatric
disorders, and other disorders.

[0100] The present invention is directed to processes for the preparation
of compounds of formula (I)

##STR00029##

[0101] wherein R1, m and R2 are as herein defined; and
pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs,
and pharmaceutically active metabolites thereof. The compounds of formula
(I) are useful in the treatment of histamine H3 receptor modulated
diseases, disorders and/or conditions, including but not limited to
cognitive disorders, sleep disorders, psychiatric disorders and other
disorders.

[0102] The present invention is directed to processes for the preparation
of compounds of formula (I-E)

##STR00030##

[0103] wherein m is 2 and wherein R1, R2 are as herein defined;
and pharmaceutically acceptable salts, pharmaceutically acceptable
prodrugs, and pharmaceutically active metabolites thereof. The compounds
of formula (I-E) are useful in the treatment of histamine H3 receptor
modulated diseases, disorders and/or conditions, including but not
limited to cognitive disorders, sleep disorders, psychiatric disorders
and other disorders.

[0104] The present invention is further directed to processes for the
preparation of compounds of formula (X), including for example, the
compound of formula (X-S), useful as intermediates in the synthesis of
compounds of formula (I). In an example, the compound of formula (X-S) is
useful as an intermediate in the synthesis of compounds (I-A), (I-B),
(I-C) and pharmaceutically acceptable salts thereof. The present
invention is further directed to process for the purification and
isolation of a compound of formula (X-S), as described in more detail
hereinafter.

[0105] The present invention is further directed to novel crystalline HCl
salts of compound (I-B), more particularly FORM I and FORM II as
described in more detail hereinafter. The present invention is further
directed to a process for the preparation of the novel crystalline HCl
salts of compound (I-B). The present invention is further directed to a
novel crystalline HCl salt of compound (I-C). The present invention is
further directed to a process for the preparation of the novel
crystalline HCl salt of compound (I-C).

[0106] In preferred embodiments of the present invention, R1 is
methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl. In
other preferred embodiments, R1 is methyl or isopropyl. In still
other preferred embodiments, R1 is isopropyl, cyclopropyl,
cyclobutyl, or cyclopentyl. In still other preferred embodiments, R1
is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In still other
preferred embodiments, R1 is cyclopropyl or cyclobutyl.

[0107] In certain preferred embodiments, m is 1. In other preferred
embodiments, m is 2.

[0108] In certain preferred embodiments, R2 is --OCHR3R4.
In other preferred embodiments, R2 is --Z--Ar.

[0109] In certain preferred embodiments, R3 is --H and R4 is
cyclopropyl, cyclocyclobutyl, or 3-methyl-oxetan-3-yl. In other
embodiments, R3 and R4 are taken together with the carbon to
which they are attached to form cyclobutyl, cyclopentyl, cyclohexyl,
tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, tetrahydrothiophenyl,
tetrahydrothiopyranyl, pyrrolidinyl, thiepanyl, piperidinyl, or azepanyl,
unsubstituted or substituted with methyl, ethyl, isopropyl, or acetyl.

[0110] In still other embodiments, --OCHR3R4 is selected from
the group consisting of tetrahydro-furan-3-yloxy,
3-methyl-oxetan-3-ylmethoxy, cyclopentyloxy, cyclohexyloxy,
tetrahydro-pyran-4-yloxy, tetrahydro-pyran-3-yloxy, cyclobutyloxy,
oxepan-4-yloxy, oxepan-3-yloxy, cyclobutylmethoxy, cyclopropylmethoxy,
tetrahydro-thiophen-3-yloxy, tetrahydro-thiopyran-4-yloxy,
1-methyl-pyrrolidin-3-yloxy, 1-acetyl-pyrrolidin-3-yloxyl,
thiepan-3-yloxy, thiepan-4-yloxy, 1-methyl-piperidin-4-yloxy,
1-acetyl-piperidin-4-yloxy, 1-isopropyl-azepan-4-yloxy,
1-acetyl-azepan-4-yloxy, 1-ethyl-azepan-3-yloxy, or
1-acetyl-azepan-3-yloxy. In still other embodiments, --OCHR3R4
is tetrahydro-furan-3-yloxy, 3-methyl-oxetan-3-ylmethoxy, cyclopentyloxy,
cyclohexyloxy, and tetrahydro-pyran-4-yloxy. In still other preferred
embodiments, --OCHR3R4 is tetrahydro-pyran-4-yloxy and m is 2.

[0111] In certain preferred embodiments, Z is O. In other preferred
embodiments, Z is S.

[0112] In certain preferred embodiments, Ar is selected from the group
consisting of a phenyl, pyrrolyl, furanyl, thiophenyl, imidazolyl,
pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, and
pyrazinyl group; wherein each Ar may be unsubstituted or substituted with
one, two, or three R5 substituents. In other preferred embodiments,
Ar is a phenyl group unsubstituted or substituted with one, two, or three
R5 substituents. In still other preferred embodiments, Ar is a
4-halophenyl group. In further preferred embodiments, Ar is selected from
the group consisting of phenyl, 3,4-dichlorophenyl,
4-methylsulfanylphenyl, 3-chlorophenyl, 3-fluorophenyl,
4-chloro-3-methylphenyl, 3-cyanophenyl, 4-chlorophenyl, 4-fluorophenyl,
3,4-difluorophenyl, 2-fluorophenyl, 3-chlorophenyl, 2,4-difluorophenyl,
3,5-dichlorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl,
3-methyl-4-methylsulfanylphenyl, and 3-pyridyl.

[0113] In certain embodiments of the present invention, the compound of
formula (I) is selected from the group consisting of
(4-cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-met-
hanone; 3-[5-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-pyridin-2-yloxy]-ben-
zonitrile; and
(4-cyclobutyl-[1,4]diazepan-1-yl)-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-
-yl]-methanone; and pharmaceutically acceptable salts, prodrugs and active
metabolites thereof.

[0114] In certain preferred embodiments, the compound of formula (I) is
selected from the group consisting of compound (I-A), compound (I-B),
compound (I-C) and pharmaceutically acceptable salts thereof.

[0115] In certain preferred embodiments, the compound of formula (I) is
one or more selected from the group consisting of

[0119] The term "halogen" represents chlorine, fluorine, bromine or
iodine.

[0120] The term "halo" represents chloro, fluoro, bromo or iodo.

[0121] The term "alkyl" refers to a straight- or branched-chain alkyl
group having from 1 to 12 carbon atoms in the chain. Examples of alkyl
groups include methyl (Me, which also may be structurally depicted by /),
ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl
(tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that
in light of the ordinary skill in the art and the teachings provided
herein would be considered equivalent to any one of the foregoing
examples.

[0122] The term "cycloalkyl" refers to a saturated monocyclic carbocycle
having from 3 to 10 ring atoms per carbocycle. Illustrative examples of
cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl.

[0123] The term "heteroaryl" refers to a monocyclic aromatic heterocycle
(ring structure having ring atoms selected from carbon atoms and up to
four heteroatoms selected from nitrogen, oxygen, and sulfur) having from
3 to 12 ring atoms per heterocycle. Illustrative examples of heteroaryl
groups include furyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridyl,
pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl.

[0124] A "heterocycloalkyl" refers to a monocyclic ring structure that is
saturated or partially saturated and has from 4 to 7 ring atoms per ring
structure selected from carbon atoms and up to two heteroatoms selected
from nitrogen, oxygen, and sulfur. The ring structure may optionally
contain up to two oxo groups on sulfur ring members. Illustrative
entities, in the form of properly bonded moieties, include:

##STR00031##

[0125] Those skilled in the art will recognize that the species of
cycloalkyl, heterocycloalkyl, and heteroaryl groups listed or illustrated
above are not exhaustive, and that additional species within the scope of
these defined terms may also be selected.

[0126] The term "substituted" means that the specified group or moiety
bears one or more substituents. The term "unsubstituted" means that the
specified group bears no substituents. The term "optionally substituted"
means that the specified group is unsubstituted or substituted by one or
more substituents. Where the term "substituted" is used to describe a
structural system, the substitution is meant to occur at any
valency-allowed position on the system. In cases where a specified moiety
or group is not expressly noted as being optionally substituted or
substituted with any specified substituent, it is understood that such a
moiety or group is intended to be unsubstituted.

[0127] Any formula given herein is intended to represent compounds having
structures depicted by the structural formula as well as certain
variations or forms. In particular, compounds of any formula given herein
may have asymmetric centers and therefore exist in different enantiomeric
forms. All optical isomers and stereoisomers of the compounds of the
general formula, and mixtures thereof, are considered within the scope of
the formula. Thus, any formula given herein is intended to represent a
racemate, one or more enantiomeric forms, one or more diastereomeric
forms, one or more atropisomeric forms, and mixtures thereof.
Furthermore, certain structures may exist as geometric isomers (i.e., cis
and trans isomers), as tautomers, or as atropisomers. Additionally, any
formula given herein is intended to embrace hydrates, solvates, and
polymorphs of such compounds, and mixtures thereof.

[0128] Any formula given herein is also intended to represent unlabeled
forms as well as isotopically labeled forms of the compounds.
Isotopically labeled compounds have structures depicted by the formulas
given herein except that one or more atoms are replaced by an atom having
a selected atomic mass or mass number. Examples of isotopes that can be
incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and
iodine, such as 2H, 3H, 11C, 13C, 14C, 15N,
18O, 17O, 31P, 32P, 35S, 18F, 36Cl,
125I, respectively. Such isotopically labeled compounds are useful
in metabolic studies (preferably with 14C), reaction kinetic studies
(with, for example 2H or 3H), detection or imaging techniques
[such as positron emission tomography (PET) or single-photon emission
computed tomography (SPECT)] including drug or substrate tissue
distribution assays, or in radioactive treatment of patients. In
particular, an 18F or 11C labeled compound may be particularly
preferred for PET or SPECT studies. Further, substitution with heavier
isotopes such as deuterium (i.e., 2H) may afford certain therapeutic
advantages resulting from greater metabolic stability, for example
increased in vivo half-life or reduced dosage requirements. Isotopically
labeled compounds of this invention and prodrugs thereof can generally be
prepared by carrying out the procedures disclosed in the schemes or in
the examples and preparations described below by substituting a readily
available isotopically labeled reagent for a non-isotopically labeled
reagent.

[0129] When referring to any formula given herein, the selection of a
particular moiety from a list of possible species for a specified
variable is not intended to define the moiety for the variable appearing
elsewhere. In other words, where a variable appears more than once, the
choice of the species from a specified list is independent of the choice
of the species for the same variable elsewhere in the formula.

[0130] Where the compounds according to this invention have at least one
chiral center, they may accordingly exist as enantiomers. Where the
compounds possess two or more chiral centers, they may additionally exist
as diastereomers. It is to be understood that all such isomers and
mixtures thereof are encompassed within the scope of the present
invention. Preferably, wherein the compound is present as an enantiomer,
the enantiomer is present at an enantiomeric excess of greater than or
equal to about 80%, more preferably, at an enantiomeric excess of greater
than or equal to about 90%, more preferably still, at an enantiomeric
excess of greater than or equal to about 95%, more preferably still, at
an enantiomeric excess of greater than or equal to about 98%, most
preferably, at an enantiomeric excess of greater than or equal to about
99%. Similarly, wherein the compound is present as a diastereomer, the
diastereomer is present at an diastereomeric excess of greater than or
equal to about 80%, more preferably, at an diastereomeric excess of
greater than or equal to about 90%, more preferably still, at an
diastereomeric excess of greater than or equal to about 95%, more
preferably still, at an diastereomeric excess of greater than or equal to
about 98%, most preferably, at an diastereomeric excess of greater than
or equal to about 99%.

[0131] Furthermore, some of the crystalline forms for the compounds of the
present invention may exist as polymorphs and as such are intended to be
included in the present invention. In addition, some of the compounds of
the present invention may form solvates with water (i.e., hydrates) or
common organic solvents, and such solvates are also intended to be
encompassed within the scope of this invention.

[0148] As used herein, unless otherwise noted, the term "isolated form"
shall mean that the compound is present in a form which is separate from
any solid mixture with another compound(s), solvent system or biological
environment. In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I) as an isolated
form. In another embodiment, the present invention is directed to a
process for the preparation of compound (I-A) as an isolated form. In
another embodiment, the present invention is directed to a process for
the preparation of compound (I-B) as an isolated form. In another
embodiment, the present invention is directed to a process for the
preparation of compound (I-C) as an isolated form.

[0149] As used herein, unless otherwise noted, the term "substantially
pure form" shall mean that the mole percent of impurities in the isolated
compound is less than about 5 mole percent, preferably less than about 2
mole percent, more preferably, less than about 0.5 mole percent, most
preferably, less than about 0.1 mole percent. In an embodiment, the
present invention is directed to a process for the preparation of a
compound of formula (I) as a substantially pure form. In another
embodiment, the present invention is directed to a process for the
preparation of compound (I-A) as a substantially pure form. In another
embodiment, the present invention is directed to a process for the
preparation of compound (I-B) as a substantially pure form. In another
embodiment, the present invention is directed to a process for the
preparation of compound (I-C) as a substantially pure form.

[0150] As used herein, unless otherwise noted, the term "substantially
free of a corresponding salt form(s)" when used to described the compound
of formula (I) shall mean that mole percent of the corresponding salt
form(s) in the isolated base of formula (I) is less than about 5 mole
percent, preferably less than about 2 mole percent, more preferably, less
than about 0.5 mole percent, most preferably less than about 0.1 mole
percent. In an embodiment, the present invention is directed to a process
for the preparation of a compound of formula (I) in a form which is
substantially free of corresponding salt forms. In another embodiment,
the present invention is directed to a process for the preparation of
compound (I-A) in a form which is substantially free of corresponding
salt forms. In another embodiment, the present invention is directed to a
process for the preparation of compound (I-B) in a form which is
substantially free of corresponding salt forms. In another embodiment,
the present invention is directed to a process for the preparation of
compound (I-C) in a form which is substantially free of corresponding
salt forms.

[0152] If the compound of Formula (I) contains a basic nitrogen, the
desired pharmaceutically acceptable salt may be prepared by any suitable
method available in the art, for example, treatment of the free base with
an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric
acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the
like, or with an organic acid, such as acetic acid, phenylacetic acid,
propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,
hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric
acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic
acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as
glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as
mandelic acid, citric acid, or tartaric acid, an amino acid, such as
aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid,
2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid,
such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic
acid, ethanesulfonic acid, any compatible mixture of acids such as those
given as examples herein, and any other acid and mixture thereof that are
regarded as equivalents or acceptable substitutes in light of the
ordinary level of skill in this technology.

[0153] If the compound of Formula (I) is an acid, such as a carboxylic
acid or sulfonic acid, the desired pharmaceutically acceptable salt may
be prepared by any suitable method, for example, treatment of the free
acid with an inorganic or organic base, such as an amine (primary,
secondary or tertiary), an alkali metal hydroxide, alkaline earth metal
hydroxide, any compatible mixture of bases such as those given as
examples herein, and any other base and mixture thereof that are regarded
as equivalents or acceptable substitutes in light of the ordinary level
of skill in this technology. Illustrative examples of suitable salts
include organic salts derived from amino acids, such as glycine and
arginine, ammonia, carbonates, bicarbonates, primary, secondary, and
tertiary amines, and cyclic amines, such as benzylamines, pyrrolidines,
piperidine, morpholine, and piperazine, and inorganic salts derived from
sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc,
aluminum, and lithium.

[0154] The invention also relates to pharmaceutically acceptable prodrugs
of the compounds of Formula (I), and treatment methods employing such
pharmaceutically acceptable prodrugs. The term "prodrug" means a
precursor of a designated compound that, following administration to a
subject, yields the compound in vivo via a chemical or physiological
process such as solvolysis or enzymatic cleavage, or under physiological
conditions (e.g., a prodrug on being brought to physiological pH is
converted to the compound of Formula (I)). A "pharmaceutically acceptable
prodrug" is a prodrug that is non-toxic, biologically tolerable, and
otherwise biologically suitable for administration to the subject.
Illustrative procedures for the selection and preparation of suitable
prodrug derivatives are described, for example, in Design of Prodrugs, H.
Bundgaard (Editor), Elsevier, 1985.

[0155] Examples of prodrugs include compounds having an amino acid
residue, or a polypeptide chain of two or more (e.g., two, three or four)
amino acid residues, covalently joined through an amide or ester bond to
a free amino, hydroxy, or carboxylic acid group of a compound of Formula
(I). Examples of amino acid residues include the twenty naturally
occurring amino acids, commonly designated by three letter symbols, as
well as 4-hydroxyproline, hydroxylysine, demosine, isodemosine,
3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,
citrulline homocysteine, homoserine, ornithine and methionine sulfone.

[0156] Additional types of prodrugs may be produced, for instance, by
derivatizing free carboxyl groups of structures of Formula (I) as amides
or alkyl esters. Examples of amides include those derived from ammonia,
primary C1-6alkyl amines and secondary di(C1-6alkyl) amines.
Secondary amines include 5- or 6-membered heterocycloalkyl or heteroaryl
ring moieties. Examples of amides include those that are derived from
ammonia, C1-3alkyl primary amines, and di(C1-2alkyl)amines.
Examples of esters of the invention include C1-7alkyl,
C5-7cycloalkyl, phenyl, and phenyl(C1-6alkyl) esters. Preferred
esters include methyl esters. Prodrugs may also be prepared by
derivatizing free hydroxy groups using groups including hemisuccinates,
phosphate esters, dimethylaminoacetates, and
phosphoryloxymethyloxycarbonyls, following procedures such as those
outlined in FLEISHER, D., et al., "Improved oral drug delivery:
solubility limitations overcome by the use of prodrugs", Adv. Drug
Delivery Rev., 1996, pp 115-130, vol. 19. Carbamate derivatives of
hydroxy and amino groups may also yield prodrugs. Carbonate derivatives,
sulfonate esters, and sulfate esters of hydroxy groups may also provide
prodrugs. Derivatization of hydroxy groups as (acyloxy)methyl and
(acyloxy)ethyl ethers,

[0157] wherein the acyl group may be an alkyl ester, optionally
substituted with one or more ether, amine, or carboxylic acid
functionalities, or where the acyl group is an amino acid ester as
described above, is also useful to yield prodrugs. Prodrugs of this type
may be prepared as described in ROBINSON, R. P., et al., "Discovery of
the hemifumarate and (alpha-L-alanyloxy)methyl ether as prodrugs of an
antirheumatic oxindole: prodrugs for the enolic OH group", J. Med. Chem.,
1996, pp 10-18, vol. 39. Free amines can also be derivatized as amides,
sulfonamides or phosphonamides. All of these prodrug moieties may
incorporate groups including ether, amine, and carboxylic acid
functionalities.

[0159] The compounds of formula (I) and their pharmaceutically acceptable
salts, pharmaceutically acceptable prodrugs, and pharmaceutically active
metabolites of the present invention are useful as modulators of the
histamine H3 receptor in the methods of the invention. As such
modulators, the compounds may act as antagonists, agonists, or inverse
agonists. "Modulators" include both inhibitors and activators, where
"inhibitors" refer to compounds that decrease, prevent, inactivate,
desensitize or down-regulate histamine H3 receptor expression or
activity, and "activators" are compounds that increase, activate,
facilitate, sensitize, or up-regulate histamine H3 receptor
expression or activity.

[0160] The term "treat" or "treating" as used herein is intended to refer
to administration of an active agent or composition of the invention to a
subject for the purpose of effecting a therapeutic or prophylactic
benefit through modulation of histamine H3 receptor activity.
Treating includes reversing, ameliorating, alleviating, inhibiting the
progress of, lessening the severity of, or preventing a disease,
disorder, or condition, or one or more symptoms of such disease, disorder
or condition mediated through modulation of histamine H3 receptor
activity. The term "subject" refers to a mammalian patient in need of
such treatment, such as a human.

[0161] Accordingly, the invention relates to methods of using the
compounds described herein to treat subjects diagnosed with or suffering
from a disease, disorder, or condition mediated by histamine H3
receptor activity, such as: cognitive disorders, sleep disorders,
psychiatric disorders, and other disorders. Symptoms or disease states
are intended to be included within the scope of "medical conditions,
disorders, or diseases."

[0166] Particularly, as modulators of the histamine H3 receptor, the
compounds prepared according to the processes of the present invention
are useful in the treatment or prevention of depression, disturbed sleep,
narcolepsy, fatigue, lethargy, cognitive impairment, memory impairment,
memory loss, learning impairment, attention-deficit disorders, and eating
disorders.

[0167] In treatment methods according to the invention, an effective
amount of at least one compound according to the invention is
administered to a subject suffering from or diagnosed as having such a
disease, disorder, or condition. An "effective amount" means an amount or
dose sufficient to generally bring about the desired therapeutic or
prophylactic benefit in patients in need of such treatment for the
designated disease, disorder, or condition. Effective amounts or doses of
the compounds of the present invention may be ascertained by routine
methods such as modeling, dose escalation studies or clinical trials, and
by taking into consideration routine factors, e.g., the mode or route of
administration or drug delivery, the pharmacokinetics of the compound,
the severity and course of the disease, disorder, or condition, the
subject's previous or ongoing therapy, the subject's health status and
response to drugs, and the judgment of the treating physician. An example
of a dose is in the range of from about 0.001 to about 200 mg of compound
per kg of subject's body weight per day, or any range therein, preferably
about 0.01 to about 10 mg/kg/day, or about 0.01 to about 1.0 mg/kg/day,
or any range therein, in single or divided dosage units (e.g., BID, TID,
QID). For a 70-kg human, an illustrative range for a suitable dosage
amount is from about 0.1 to about 100 mg/day, or any range therein,
preferably from about 0.5 to about 50.0 mg/day.

[0168] Once improvement of the patient's disease, disorder, or condition
has occurred, the dose may be adjusted for preventative or maintenance
treatment. For example, the dosage or the frequency of administration, or
both, may be reduced as a function of the symptoms, to a level at which
the desired therapeutic or prophylactic effect is maintained. Of course,
if symptoms have been alleviated to an appropriate level, treatment may
cease. Patients may, however, require intermittent treatment on a
long-term basis upon any recurrence of symptoms.

[0169] As more extensively provided in this written description, terms
such as "reacting" and "reacted" are used herein in reference to a
chemical entity that is any one of: (a) the actually recited form of such
chemical entity, and (b) any of the forms of such chemical entity in the
medium in which the compound is being considered when named.

[0170] One skilled in the art will recognize that, where not otherwise
specified, the reaction step(s) is performed under suitable conditions,
according to known methods, to provide the desired product. One skilled
in the art will further recognize that, in the specification and claims
as presented herein, wherein a reagent or reagent class/type (e.g. base,
solvent, etc.) is recited in more than one step of a process, the
individual reagents are independently selected for each reaction step and
may be the same of different from each other. For example wherein two
steps of a process recite an organic or inorganic base as a reagent, the
organic or inorganic base selected for the first step may be the same or
different than the organic or inorganic base of the second step.

[0171] Further, one skilled in the art will recognize that wherein a
reaction step of the present invention may be carried out in a variety of
solvents or solvent systems, said reaction step may also be carried out
in a mixture of the suitable solvents or solvent systems. One skilled in
the art will further recognize that wherein two consecutive reaction or
process steps are run without isolation of the intermediate product (i.e.
the product of the first of the two consecutive reaction or process
steps), then the first and second reaction or process steps may be run in
the same solvent or solvent system; or alternatively may be run in
different solvents or solvent systems following solvent exchange, which
may be completed according to known methods.

[0172] To provide a more concise description, some of the quantitative
expressions given herein are not qualified with the term "about". It is
understood that whether the term "about" is used explicitly or not, every
quantity given herein is meant to refer to the actual given value, and it
is also meant to refer to the approximation to such given value that
would reasonably be inferred based on the ordinary skill in the art,
including approximations due to the experimental and/or measurement
conditions for such given value.

[0173] To provide a more concise description, some of the quantitative
expressions herein are recited as a range from about amount X to about
amount Y. It is understood that wherein a range is recited, the range is
not limited to the recited upper and lower bounds, but rather includes
the full range from about amount X through about amount Y, or any range
therein.

[0174] Examples of suitable solvents, bases, reaction temperatures, and
other reaction parameters and components are provided in the detailed
descriptions which follows herein. One skilled in the art will recognize
that the listing of said examples is not intended, and should not be
construed, as limiting in any way the invention set forth in the claims
which follow thereafter.

[0175] As used herein, unless otherwise noted, the term "leaving group"
shall mean a charged or uncharged atom or group which departs during a
substitution or displacement reaction. Suitable examples include, but are
not limited to, bromo, chloro, fluoor, iodo, mesylate, tosylate, and the
like. In a preferred example, the leaving group is bromo, chloro or iodo,
more preferably, chloro.

[0176] During any of the processes for preparation of the compounds of the
present invention, it may be necessary and/or desirable to protect
sensitive or reactive groups on any of the molecules concerned. This may
be achieved by means of conventional protecting groups, such as those
described in Protective Groups in Organic Chemistry, J. F. W. McOmie
(Editor), Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts,
Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The
protecting groups may be removed at a convenient subsequent stage using
methods known from the art.

[0177] Where the processes for the preparation of the compounds according
to the invention give rise to mixture of stereoisomers, these isomers may
be separated by conventional techniques such as preparative
chromatography.

[0178] The compounds may be prepared in racemic form, or individual
enantiomers may be prepared either by enantiospecific synthesis or by
resolution. The compounds may, for example, be resolved into their
component enantiomers by standard techniques, such as the formation of
diastereomeric pairs by salt formation with an optically active acid,
such as (-)-di-p-toluoyl-D-tartaric acid and/or
(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization
and regeneration of the free base. The compounds may also be resolved by
formation of diastereomeric esters or amides, followed by chromatographic
separation and removal of the chiral auxiliary. Alternatively, the
compounds may be resolved using a chiral HPLC column.

[0179] Additionally, chiral HPLC against a standard may be used to
determine percent enantiomeric excess (% ee). The enantiomeric excess may
be calculated as follows

[(Rmoles-Smoles)/(Rmoles+Smoles)]×100%

[0180] where Rmoles and Smoles are the R and S mole fractions in the
mixture such that Rmoles+Smoles=1. The enantiomeric excess may
alternatively be calculated from the specific rotations of the desired
enantiomer and the prepared mixture as follows:

ee=([α-obs]/[α-max])×100.

[0181] The present invention is directed to processes for the preparation
of compounds of formula (X), useful as intermediates in the synthesis of
the compounds of formula (I), as outlined in more detail in Schemes 1
through 4, which follow herein. The present invention is further directed
to processes for the preparation of compounds of formula (I) from
suitably substituted compounds of formula (X), as outlined in more detail
in Schemes 5 through 7, which follow herein.

[0182] The present invention is directed to a process for the preparation
of compounds of formula (X) as outlined in more detail in Scheme 1,
below.

##STR00032##

[0183] Accordingly, a suitably substituted compound of formula (V), a
known compound or compound prepared by known methods is reacted with a
suitably substituted compound of formula (VI), wherein LG1 is a
suitably selected first leaving group such as chloro, bromo, fluoro, and
the like, preferably chloro, and wherein LG2 is a second leaving
group such OC1-4alkyl, --O-phenyl, --O-benzyl, chloro,
dimethylamino, diethylamino, and the like, preferably --O-methyl or
--O-ethyl; a known compound or compound prepared by known methods;
wherein the compound of formula (V) is present in an amount in the range
of from about 1.0 to about 5.0 molar equivalents (relative to moles of
the compound of formula (VI), more preferably in an amount in the range
of from about 2.0 to about 3.0 molar equivalents, more preferably about
2.5 molar equivalents;

[0184] in the presence of a suitably selected base such as an alkyl
lithium, such as n-hexyl lithium, n-butyl lithium and the like, or in the
presence of a suitably selected base such as a lithium alkoxide or sodium
alkoxide such as lithium ethoxide, lithium methoxide, sodium methoxide,
and the like, or in the presence of a suitably selected base such as
isopropyl magnesium chloride, and the like; preferably the base is an
alkyl lithium, more preferably, the base is n-hexyl lithium; and when the
base is an alkyl lithium, the base is preferably present in an amount in
the range of from about 0.1 to about 3.0 molar equivalents (relative to
the moles of the compound of formula (VI), more preferably in an amount
in the range of form about 0.1 to about 1.0 molar equivalents, more
preferably about 0.5 molar equivalents; and wherein the and when the base
is a lithium alkoxide or sodium alkoxide, the base is preferably present
in an amount in the range of from about 0.5 to about 3.0 molar
equivalents (relative to the moles of the compound of formula (VI), more
preferably in an amount in the range of form about 0.5 to about 1.5 molar
equivalents, more preferably about 1.0 molar equivalents;

[0185] in an organic solvent such as THF, toluene, 2-methyl-THF, MTBE, and
the like, preferably THF; preferably at a temperature in the range of
from about 0° C. to about room temperature, more preferably at
about 0° C.; to yield the corresponding compound of formula (VII).

[0186] Preferably, wherein the base is an alkyl lithium such as n-hexyl
lithium, and the like, the compound of formula (VI) is added to a mixture
of the compound of formula (V) and the organic solvent; followed by
addition of the base to the resulting mixture. Preferably, LG1,
LG2, the base, the organic solvent and any other reaction conditions
are selected to minimize the amount of byproducts.

[0187] In an embodiment of the present invention, the compound of formula
(V) is reacted with the compound of formula (VI) in the presence of an
alkyl lithium, preferably in the presence of n-hexyl lithium. In another
embodiment of the present invention, the compound of formula (V) is
reacted with the compound of formula (VI) in the presence of a lithium
alkoxide, preferably in the presence of lithium methoxide.

[0188] The compound of formula (VII) is reacted with a suitably selected
aldehyde or ketone derivative of the desired R1 substituent group
(more particularly, to a suitably selected aldehyde derivative of
C1-4alkyl or a suitably selected ketone derivative of
C3-10cycloalkyl), a known compound or compound prepared by known
methods; wherein the aldehyde or ketone derivative of the desired R1
substituent group is preferably present in an amount in the range of from
about 1.0 to about 3.0 molar equivalents (relative to the moles of the
compound of formula (VII)), more preferably in an amount in the range of
from about 1.0 to about 2.0 molar equivalents, more preferably in an
amount of about 1.3 molar equivalents;

[0189] in the presence of a suitably substituted reducing agent such as
sodium triacetoxyborohydride, sodium cyanoborohydride, and the like,
preferably sodium triacetoxyborohydride; wherein the reducing agent is
preferably present in an amount in the range of from about 1.0 to about
3.0 molar equivalents (relative to the moles of the compound of formula
(VII)), more preferably in an amount in the range of from about 1.0 to
about 2.0 molar equivalents, more preferably in an amount of about 1.3
molar equivalents;

[0190] in an organic solvent such as DCE, THF, 2-methyl-THF, and the like,
preferably DCE; preferably at about room temperature; to yield the
corresponding compound of formula (X).

[0191] Preferably, the aldehyde or ketone derivative of the desired
R1 substituent group is added to a mixture of the compound of
formula (VII) and the organic solvent, followed by addition of the
reducing agent.

[0192] In an embodiment, the present invention is directed to a process
for the preparation of compounds of formula (X-S) as outlined in more
detail in Scheme 2, below.

##STR00033##

[0193] Accordingly, a compound of formula (V-S), a known compound or
compound prepared by known methods is reacted with a suitably substituted
compound of formula (VI-S), wherein LG1 is a suitably selected first
leaving group such as chloro, bromo, fluoro, and the like, preferably
chloro, and wherein LG2 is a second leaving group such
OC1-4alkyl, --O-phenyl, --O-benzyl, chloro, dimethylamino,
diethylamino, and the like, preferably --O-methyl or --O-ethyl; wherein
the compound of formula (V-S) is present in an amount in the range of
from about 1.0 to about 5.0 molar equivalents (relative to moles of the
compound of formula (VI-S), more preferably in an amount in the range of
from about 2.0 to about 3.0 molar equivalents, more preferably about 2.5
molar equivalents;

[0194] in the presence of a suitably selected base such as an alkyl
lithium, such as n-hexyl lithium, n-butyl lithium and the like, or in the
presence of a suitably selected base such as a lithium alkoxy or sodium
alkoxide such as lithium ethoxide, lithium methoxide, sodium methoxide,
and the like, or in the presence of a suitably selected base such as
isopropyl magnesium chloride, and the like; preferably the base is an
alkyl lithium, more preferably, the base is n-hexyl lithium; and when the
base is an alkyl lithium, the base is preferably present in an amount in
the range of from about 0.1 to about 3.0 molar equivalents (relative to
the moles of the compound of formula (VI-S), more preferably in an amount
in the range of form about 0.1 to about 1.0 molar equivalents, more
preferably about 0.5 molar equivalents; and wherein the and when the base
is a lithium alkoxy or sodium alkoxide, the base is preferably present in
an amount in the range of from about 0.5 to about 3.0 molar equivalents
(relative to the moles of the compound of formula (VI-S), more preferably
in an amount in the range of form about 0.5 to about 1.5 molar
equivalents, more preferably about 1.0 molar equivalents;

[0195] in an organic solvent such as THF, toluene, 2-methyl-THF, MTBE, and
the like, preferably THF; preferably at a temperature in the range of
from about 0° C. to about room temperature, more preferably at
about 0° C.; to yield the corresponding compound of formula
(VII-S).

[0196] Preferably, wherein the base is an alkyl lithium such as n-hexyl
lithium and the like, the compound of formula (VI-S) is added to a
mixture of the compound of formula (V-S) and the organic solvent;
followed by addition of the base to the resulting mixture. Preferably,
LG1, LG2, the base, the organic solvent and any other reaction
conditions are selected to minimize the amount of byproducts.

[0197] In an embodiment of the present invention, the compound of formula
(V-S) is reacted with the compound of formula (VI-S) in the presence of
an alkyl lithium, preferably in the presence of n-hexyl lithium. In
another embodiment of the present invention, the compound of formula
(V-S) is reacted with the compound of formula (VI-S) in the presence of a
lithium alkoxide, preferably in the presence of lithium methoxide.

[0198] The compound of formula (VII-S) is reacted with a compound of
formula (VIII-S) (a suitably selected ketone derivative of the desired
R1 substituent group), a known compound or compound prepared by
known methods; wherein the compound of formula (VIII-S) is preferably
present in an amount in the range of from about 1.0 to about 3.0 molar
equivalents (relative to the moles of the compound of formula (VII-S)),
more preferably in an amount in the range of from about 1.0 to about 2.0
molar equivalents, more preferably in an amount of about 1.3 molar
equivalents;

[0199] in the presence of a suitably substituted reducing agent such as
sodium triacetoxyborohydride, sodium cyanoborohydride, and the like,
preferably sodium triacetoxyborohydride; wherein the reducing agent is
preferably present in an amount in the range of from about 1.0 to about
3.0 molar equivalents (relative to the moles of the compound of formula
(VII-S)), more preferably in an amount in the range of from about 1.0 to
about 2.0 molar equivalents, more preferably in an amount of about 1.3
molar equivalents;

[0200] in an organic solvent such as DCE, THF, 2-methyl-THF, and the like,
preferably DCE; preferably at about room temperature; to yield the
corresponding compound of formula (X-S).

[0201] Preferably, the compound of formula (VIII-S) is added to a mixture
of the compound of formula (VII-S) and the organic solvent, followed by
addition of the reducing agent.

[0202] In an embodiment, the present invention is directed to a process
for the purification of the compound of formula (X-S), which process
comprising the following steps:

[0203] STEP A: reacting the compound of formula (X-S) with L-tartaric
acid; wherein the L-tartaric acid is preferably present in an amount in
the range of form about 0.5 to about 2.0 molar equivalents, more
preferably in an amount in the range of from about 1.0 to about 1.5 molar
equivalents, more preferably in an amount of about 1.05 molar
equivalents; in an organic solvent such as ethanol, acetonitrile, IPA,
and the like, preferably ethanol; preferably at a temperature in the
range of from about 20° C. to about solvent reflux temperature,
more preferably at about 80° C.; to yield the corresponding
tartaric acid salt of the compound of formula (IX-S), preferably as a
solid; preferably the solid is isolated by filtration;

[0204] STEP B: reacting the tartaric acid salt of the compound of formula
(X-S) (prepared as in STEP A) with a suitably selected base such as
sodium hydroxide, potassium hydroxide, sodium carbonate, and the like,
preferably sodium hydroxide; wherein the base is preferably present in an
amount in the range of from about 1.0 to about 5.0 molar equivalents,
more preferably in an amount in the range of from about 2.5 to about 5.0,
more preferably in an amount of about 3.9 molar equivalents; in an
organic solvent such as isopropyl acetate, dichloromethane, 2-methyl-THF,
and the like; preferably isopropyl acetate; preferably at room
temperature; to yield the corresponding compound of formula (X-S).

[0205] The present invention is further directed to a process for the
preparation of compounds of formula (X) as outlined in more detail in
Scheme 3, below.

##STR00034##

[0206] Accordingly, a suitably substituted compound of formula (V-S), a
known compound or compound prepared by known methods, is reacted with a
suitably selected aldehyde or ketone derivative of the desired R1
substituent group (more particularly, with a suitably selected aldehyde
or ketone derivative of C1-4alkyl or a suitably selected ketone
derivative of C3-10cycloalkyl), wherein the suitably selected
aldehyde or ketone derivative of the desired R1 substituent group is
preferably present in an amount in the range of from about 0.5 to about
2.0 molar equivalents (relative to the moles of the compound of formula
(V-S)), more preferably in an amount in the range of from about 1.0 to
about 1.5 molar equivalents, more preferably in an amount of about 1.05
molar equivalents;

[0207] neat or in an organic solvent such as toluene, THF, 2-methyl-THF,
hexane, and the like, preferably toluene; preferably at a temperature in
the range of from about room temperature to about reflux temperature,
more preferably at an elevated temperature of greater than about
40° C., more preferably at about reflux temperature; to yield the
corresponding compound of formula (IX).

[0208] The compound of formula (IX) is reacted with a suitably selected
reducing agent such as sodium borohydride, potassium borohydride, lithium
borohydride, sodium triacetoxyborohydride, and the like, preferably
sodium borohydride; wherein the reducing agent is preferably present in
an amount in the range of from about 0.5 to about 1.5 molar equivalents
(relative to the amount of the compound of formula (IX), more preferably
in an amount of about 1.0 molar equivalents; wherein the reducing agent
is preferably added as a solution in water, stabilized with a suitably
selected base such as sodium hydroxide in an amount of about 0.1
equivalents;

[0209] optionally in the presence of an acid such as HCl, acetic acid,
sulfuric acid, trifluoroacetic acid, and the like, preferably HCl;
preferably, the acid is not substantially reduced under the conditions of
the reaction, more preferably, the acid is not reduced under the
conditions of the reaction; wherein the acid is preferably present in an
amount in the range of from about 1.0 to about 5.0 molar equivalents
(relative to the moles of the compound of formula (IX)), more preferably
in an amount in the range of from about 3.0 to about 5.0 molar
equivalents, more preferably in an amount of about 4.0 molar equivalents;

[0210] neat, in water or an aqueous organic solvent such as methanol,
ethanol, isopropanol, THF, acetonitrile, and the like; preferably at a
temperature in the range of from about -10° C. to about 0°
C., more preferably at about -5° C.; to yield the corresponding
compound of formula (XI).

[0211] Preferably, wherein the reducing agent is lithium borohydride, the
compound of formula (IX) is reacted with the reducing agent in the
absence of the acid.

[0212] The compound of formula (XI) is reacted with a suitably substituted
compound of formula (VI), wherein LG1 is a suitably selected first
leaving group such as chloro, bromo, fluoro, and the like, preferably
chloro, and wherein LG2 is a second leaving group such
O--C1-4alkyl, --O-phenyl, --O-benzyl, chloro, fluoro, bromo, and the
like, preferably chloro; wherein preferably, LG2 is more reactive
than LG1 under the reaction conditions; and wherein the compound of
formula (VI) is present in an amount in the range of from about 0.5 to
about 2.0 molar equivalents (relative to moles of the compound of formula
(IX)), more preferably in an amount in the range of from about 1.0 to
about 1.5 molar equivalents, more preferably about 1.05 molar
equivalents;

[0213] in an organic solvent such as MTBE, toluene, THF, 2-methyl-THF, and
the like, preferably toluene or 2-methyl-THF; preferably at a temperature
in the range of from about room temperature to about 50° C., more
preferably at a temperature in the range of form about 0° C. to
about 35° C.; to yield the corresponding compound of formula
(X-E).

[0214] Alternatively, the compound of formula (XI), is reacted with a
suitably substituted compound of formula (VI), wherein LG1 is a
suitably selected first leaving group such as chloro, bromo, fluoro, and
the like, preferably chloro, and wherein LG2 is a second leaving
group such O--C1-4alkyl, --O-phenyl, --O-benzyl, chloro, fluoro,
bromo, and the like, preferably chloro; wherein preferably, LG2 is
more reactive than LG1 under the reaction conditions; and wherein
the compound of formula (VI) is present in an amount in the range of from
about 0.5 to about 2.0 molar equivalents (relative to moles of the
compound of formula (IX)), more preferably in an amount in the range of
from about 1.0 to about 1.5 molar equivalents, more preferably about 1.05
molar equivalents;

[0215] in the presence of a suitably selected base, preferably a suitably
selected inorganic base such as NaOH, KOH, LiOH, sodium carbonate,
potassium carbonate, cesium carbonate, sodium phosphate, potassium
phosphate, and the like, more preferably NaOH, more preferably 30% NaOH;
wherein the base is preferably present in an amount greater than 1 molar
equivalent (relative to the moles of the compound of formula (VI)), more
preferably in an amount in the range of from about 1.05 to about 2.5
molar equivalents, more preferably in an amount in the range of from
about 1.5 to about 2 molar equivalents;

[0216] in a mixture of water and a suitably selected organic solvent such
as MTBE, 2-methyl-THF, toluene, and the like; preferably at a temperature
of less than about 30° C., more preferably at a temperature in the
range of from about 0° C. to about 20° C., more preferably
at a temperature in the range of about 10° C. to about 15°
C.; to yield the corresponding compound of formula (X).

[0217] Preferably, the compound of formula (VI) in a suitably selected
solvent is added to an aqueous solution of the compound of formula (XI)
and the base. More preferably, the compound of formula (VI) in MTBE is
added to an aqueous solution of the compound of formula (XI) and 30%
NaOH.

[0218] One skilled in the art will recognize that when in the compound of
formula (VI) LG2 is chloro, then the compound of formula (X-E) is
prepared as its corresponding HCl salt. Further, alternate suitable
LG2 leaving groups may be selected, as would be readily understood
and recognized by one skilled in the art, to yield the compound of
formula (X-E) as the corresponding salt forms.

[0219] Alternatively, the compound of formula (IX) is reacted with a
suitably substituted compound of formula (VI), wherein LG1 is a
suitably selected first leaving group such as chloro, bromo, fluoro, and
the like, preferably chloro, and wherein LG2 is a second leaving
group such O--C1-4alkyl, --O-phenyl, --O-benzyl, chloro, fluoro,
bromo, and the like, preferably chloro; and wherein LG2 is
preferably more reactive than LG1 under the reaction conditions, a
known compound or compound prepared by known methods; wherein the
compound of formula (VI) is present in an amount in the range of from
about 0.5 to about 2.0 molar equivalents (relative to moles of the
compound of formula (IX), more preferably in an amount in the range of
from about 1.0 to about 1.5 molar equivalents, more preferably about 1.05
molar equivalents;

[0220] in the presence of a suitably selected reducing agent such as
sodium triacetoxyborohydride, sodium cyanoborohydride, sodium
borohydride, and the like, preferably sodium triacetoxyborohydride;
wherein the reducing agent is preferably present in an amount in the
range of from about 0.5 to about 2.0 molar equivalents (relative to the
moles of the compound of formula (IX)), more preferably in an amount in
the range of from about 1.0 to about 1.5 molar equivalents, more
preferably in an amount of about 1.25 molar equivalents;

[0221] optionally in the presence of an organic acid such as TFA, acetic
acid, and the like, preferably acetic acid; wherein the acid is
preferably present in an amount in the range of form about 0.5 to about
2.0 molar equivalents (relative to the moles of the compound of formula
(IX)), more preferably in an amount in the range of from about 0.5 to
about 1.5 molar equivalents, more preferably in an amount of about 1.0
molar equivalents;

[0222] in an organic solvent such as toluene, THF, acetonitrile, and the
like, preferably acetonitrile; preferably at a temperature in the range
of from about room temperature to about 50° C., more preferably at
a temperature in the range of from about room temperature to about
35° C.; to yield the corresponding compound of formula (X-E).

[0223] Preferably, the compound of formula (VI) is added to a mixture of
the compound of formula (IX) and the reducing agent, in the organic
solvent.

[0224] In an embodiment, the present invention is directed to a process
for the preparation of compounds of formula (X-S) as outlined in more
detail in Scheme 4, below.

##STR00035##

[0225] Accordingly, a compound of formula (V-S), a known compound or
compound prepared by known methods, is reacted with a compound of formula
(VIII-S) (a suitably selected ketone derivative of the desired R1
substituent group), wherein the compound of formula (VIII-S) is
preferably present in an amount in the range of from about 0.5 to about
2.0 molar equivalents (relative to the moles of the compound of formula
(V-S)), more preferably in an amount in the range of from about 1.0 to
about 1.5 molar equivalents, more preferably in an amount of about 1.05
molar equivalents;

[0226] neat or in an organic solvent such as toluene, THF, 2-methyl-THF,
hexane, and the like, preferably toluene; preferably at a temperature in
the range of from about room temperature to about reflux temperature,
more preferably at an elevated temperature of greater than about
40° C., more preferably at about reflux temperature; to yield the
corresponding compound of formula (IX-S).

[0227] The compound of formula (IX-S) is reacted with a suitably selected
reducing agent such as sodium borohydride, potassium borohydride, lithium
borohydride, sodium triacetoxyborohydride, and the like, preferably
sodium borohydride; wherein the reducing agent is preferably present in
an amount in the range of from about 0.5 to about 1.5 molar equivalents
(relative to the amount of the compound of formula (IX-S), more
preferably in an amount of about 1.0 molar equivalents; wherein the
reducing agent is preferably added as a solution in water, stabilized
with a suitably selected base such as sodium hydroxide in an amount of
about 0.1 equivalents;

[0228] optionally in the presence of an acid such as HCl, acetic acid,
sulfuric acid, trifluoroacetic acid, and the like, preferably HCl;
preferably, the acid is not substantially reduced under the conditions of
the reaction, more preferably, the acid is not reduced under the
conditions of the reaction; wherein the acid is preferably present in an
amount in the range of from about 1.0 to about 5.0 molar equivalents
(relative to the moles of the compound of formula (IX-S)), more
preferably in an amount in the range of from about 3.0 to about 5.0 molar
equivalents, more preferably in an amount of about 4.0 molar equivalents;

[0229] neat, in water or an aqueous organic solvent such as methanol,
ethanol, IPA, THF, acetonitrile, and the like; preferably at a
temperature in the range of from about -10° C. to about 0°
C., more preferably at about -5° C.; to yield the corresponding
compound of formula (XI-S).

[0230] Preferably, wherein the reducing agent is lithium borohydride, the
compound of formula (IX) is reacted with the reducing agent in the
absence of the acid.

[0231] The compound of formula (XI-S) is reacted with a suitably
substituted compound of formula (VI-S), wherein LG1 is a suitably
selected first leaving group such as chloro, bromo, fluoro, and the like,
preferably chloro, and wherein LG2 is a second leaving group such
O--C1-4alkyl, --O-phenyl, --O-benzyl, chloro, fluoro, bromo, and the
like, preferably chloro; wherein preferably, LG2 is more reactive
than LG1 under the reaction conditions; and wherein the compound of
formula (VI-S) is present in an amount in the range of from about 0.5 to
about 2.0 molar equivalents (relative to moles of the compound of formula
(IX-S)), more preferably in an amount in the range of from about 1.0 to
about 1.5 molar equivalents, more preferably about 1.05 molar
equivalents;

[0232] in an organic solvent such as MTBE, toluene, THF, 2-methyl-THF, and
the like, preferably toluene or 2-methyl-THF; preferably at a temperature
in the range of from about room temperature to about 50° C., more
preferably at a temperature in the range of form about 0° C. to
about 35° C.; to yield the corresponding compound of formula
(X-S).

[0233] One skilled in the art will recognize that when in the compound of
formula (VI-S) LG2 is chloro, then the compound of formula (X-S) is
prepared as its corresponding HCl salt. Further, alternate suitable
LG2 leaving groups may be selected, as would be readily understood
and recognized by one skilled in the art, to yield the compound of
formula (X-E) as the corresponding salt forms.

[0234] Alternatively, the compound of formula (XI-S), is reacted with a
suitably substituted compound of formula (VI-S), wherein LG1 is a
suitably selected first leaving group such as chloro, bromo, fluoro, and
the like, preferably chloro, and wherein LG2 is a second leaving
group such O--C1-4alkyl, --O-phenyl, --O-benzyl, chloro, fluoro,
bromo, and the like, preferably chloro; wherein preferably, LG2 is
more reactive than LG1 under the reaction conditions; and wherein
the compound of formula (VI-S) is present in an amount in the range of
from about 0.5 to about 2.0 molar equivalents (relative to moles of the
compound of formula (IX-S)), more preferably in an amount in the range of
from about 1.0 to about 1.5 molar equivalents, more preferably about 1.05
molar equivalents;

[0235] in the presence of a suitably selected base, preferably a suitably
selected inorganic base such as NaOH, KOH, LiOH, sodium carbonate,
potassium carbonate, cesium carbonate, sodium phosphate, potassium
phosphate, and the like, more preferably NaOH, more preferably 30% NaOH;
wherein the base is preferably present in an amount greater than 1 molar
equivalent (relative to the moles of the compound of formula (VI-S)),
more preferably in an amount in the range of from about 1.05 to about 2.5
molar equivalents, more preferably in an amount in the range of from
about 1.5 to about 2 molar equivalents;

[0236] in a mixture of water and a suitably organic selected solvent such
as MTBE, 2-methylTHF, toluene, and the like; preferably at a temperature
of less than about 30° C., more preferably at a temperature in the
range of from about 0° C. to about 20° C., more preferably
at a temperature in the range of about 10° C. to about 15°
C.; to yield the corresponding compound of formula (X-S).

[0237] Preferably, the compound of formula (VI-S) in a suitably selected
solvent is added to an aqueous solution of the compound of formula (XI-S)
and the base. More preferably, the compound of formula (VI-S) in MTBE is
added to an aqueous solution of the compound of formula (XI-S) and 30%
NaOH.

[0238] Alternatively, the compound of formula (IX-S) is reacted with a
suitably substituted compound of formula (VI-S), wherein LG1 is a
suitably selected first leaving group such as chloro, bromo, fluoro, and
the like, preferably chloro, and wherein LG2 is a second leaving
group such O--C1-4alkyl, --O-phenyl, --O-benzyl, chloro, fluoro,
bromo, and the like, preferably chloro; and wherein LG2 is
preferably more reactive than LG1 under the reaction conditions, a
known compound or compound prepared by known methods; wherein the
compound of formula (VI-S) is present in an amount in the range of from
about 0.5 to about 2.0 molar equivalents (relative to moles of the
compound of formula (IX-S)), more preferably in an amount in the range of
from about 1.0 to about 1.5 molar equivalents, more preferably about 1.05
molar equivalents;

[0239] in the presence of a suitably selected reducing agent such as
sodium triacetoxyborohydride, sodium cyanoborohydride, sodium
borohydride, and the like, preferably sodium triacetoxyborohydride;
wherein the reducing agent is preferably present in an amount in the
range of from about 0.5 to about 2.0 molar equivalents (relative to the
moles of the compound of formula (IX-S)), more preferably in an amount in
the range of from about 1.0 to about 1.5 molar equivalents, more
preferably in an amount of about 1.25 molar equivalents;

[0240] optionally in the presence of an organic acid such as TFA, acetic
acid, and the like, preferably acetic acid; wherein the acid is
preferably present in an amount in the range of form about 0.5 to about
2.0 molar equivalents (relative to the moles of the compound of formula
(IX-S)), more preferably in an amount in the range of from about 0.5 to
about 1.5 molar equivalents, more preferably in an amount of about 1.0
molar equivalents;

[0241] in an organic solvent such as toluene, THF, acetonitrile, and the
like, preferably acetonitrile; preferably at a temperature in the range
of from about room temperature to about 50° C., more preferably at
a temperature in the range of from about room temperature to about
35° C.; to yield the corresponding compound of formula (X-S).

[0242] Preferably, the compound of formula (VI-S) is added to a mixture of
the compound of formula (IX-S) and the reducing agent, in the organic
solvent.

[0243] Preferably, wherein the compound of formula (X-S) is prepared as a
free base, the compound of formula (X-S) may be reacted with for example
anhydrous HCl (or HCl gas), wherein the anhydrous HCl is dissolved in a
suitably selected organic solvent such as 2-propanol, diethyl ether, and
the like, preferably 2-propanol, to yield the corresponding compound of
formula (X-S), as its corresponding HCl salt, preferably as a solid.

[0244] The present invention is further directed to processes for the
preparation of compounds of formula (I), as outlined in more detail in
Scheme 5, below.

##STR00036##

[0245] Accordingly, a suitably substituted compound of formula (X) or its
corresponding pharmaceutically acceptable salt, prepared as for example
described herein, is reacted with a compound of formula (XII), a known
compound or compound prepared by known methods; wherein the compound of
formula (XII) is preferably present in an amount in the range of from
about 0.5 to about 2.0 molar equivalents (relative to the moles of the
compound of formula (X), more preferably in an amount in the range of
from about 1.0 to about 2.0 molar equivalents, more preferably in an
amount of about 1.1 to about 1.5 molar equivalents;

[0246] in the presence of a suitably selected first inorganic base such as
cesium carbonate, potassium carbonate, and the like, preferably cesium
carbonate; wherein the inorganic base is preferably present in an amount
in the range of from about 1.5 to about 3.0 molar equivalents (relative
to the moles of the compound of formula (X), more preferably in an amount
of about 2.0 molar equivalents;

[0247] in an organic solvent such as DMA, DMF, NMP, acetonitrile, and the
like, preferably DMA; preferably at a temperature in the range of from
about 75° C. to about reflux temperature, more preferably at a
temperature in the range of form about 90° C. to about 125°
C.; to yield the corresponding compound of formula (Ia).

[0248] Preferably the compound of formula (Ia) is further reacted with a
suitably selected acid such as HCl; in an organic solvent such as IPA; to
yield the corresponding acid addition salt of the compound of formula
(Ia).

[0249] Alternatively, a suitably substituted compound of formula (X),
prepared as for example described herein, is reacted with a compound of
formula (XIII), a known compound or compound prepared by known methods;
wherein the compound of formula (XIII) is preferably present in an amount
in the range of from about 1.0 to about 3.0 molar equivalents (relative
to the moles of the compound of formula (X)), more preferably in an
amount of about 1.2 molar equivalents;

[0250] in the presence of a suitably selected second inorganic base such
as KOH, KO-t-Bu, NaOH, NaO-t-Bu, and the like, preferably KOH; wherein
the inorganic base is preferably present in an amount in the range of
from 1.0 to about 5.0 molar equivalents (relative to the moles of the
compound of formula (X)), more preferably in an amount in the range of
from about 2.0 to about 4.0 molar equivalents, more preferably in an
amount of about 3.3 molar equivalents;

[0251] optionally in the presence of a suitably selected additive such as
a suitably selected crown ether such as 18-crown-6, or a suitably
selected additive such as diglyme, and the like; wherein the additive is
preferably present in a catalytic amount;

[0252] in an organic solvent such as toluene, THF, 2-methyl-THF, and the
like, preferably toluene; preferably at a temperature in the range of
from 60° C. to about reflux temperature, more preferably at about
reflux temperature; to yield the corresponding compound of formula (Ib).

[0253] Preferably the compound of formula (Ib) is further reacted with a
suitably selected acid such as HCl; in an organic solvent such as IPA; to
yield the corresponding acid addition salt of the compound of formula
(Ib).

[0254] In certain embodiments, the present invention is directed to
processes for the preparation of compound (I-A) and compound (I-B), as
outlined in more detail in Scheme 6, below.

##STR00037##

[0255] Accordingly, a suitably substituted compound of formula (X-S) or
its corresponding pharmaceutically acceptable salt thereof, preferably
the corresponding HCl salt of the compound of formula (X-S), prepared as
for example described herein, is reacted with a compound of formula
(XII-A), a known compound or compound prepared by known methods; wherein
the compound of formula (XII-A) is preferably present in an amount in the
range of from about 0.5 to about 2.0 molar equivalents (relative to the
moles of the compound of formula (X-S)), more preferably in an amount in
the range of from about 1.0 to about 2.0 molar equivalents, more
preferably in an amount of about 1.1 to about 1.5 molar equivalents;

[0256] in the presence of a suitably selected first inorganic base such as
cesium carbonate, potassium carbonate, and the like, preferably cesium
carbonate; wherein the inorganic base is preferably present in an amount
in the range of from about 1.5 to about 3.0 molar equivalents (relative
to the moles of the compound of formula (X-S)), more preferably in an
amount of about 2.0 molar equivalents;

[0257] in an organic solvent such as DMA, DMF, NMP, acetonitrile, and the
like, preferably DMA or DMF; preferably at a temperature in the range of
from about 75° C. to about reflux temperature, more preferably at
a temperature in the range of form about 90° C. to about
125° C.; to yield the corresponding compound (I-A).

[0258] Preferably compound (I-A) is further reacted with a suitably
selected acid such as HCl; in an organic solvent such as IPA; to yield
the corresponding salt of compound (I-A).

[0259] Alternatively, a suitably substituted compound of formula (X-S),
prepared as for example described herein, is reacted with a compound of
formula (XII-B), a known compound or compound prepared by known methods;
wherein the compound of formula (XII-B) is preferably present in an
amount in the range of from about 0.5 to about 2.0 molar equivalents
(relative to the moles of the compound of formula (X-S)), more preferably
in an amount in the range of from about 1.0 to about 2.0 molar
equivalents, more preferably in an amount of about 1.1 to about 1.5 molar
equivalents;

[0260] in the presence of a suitably selected first inorganic base such as
cesium carbonate, potassium carbonate, and the like, preferably cesium
carbonate; wherein the inorganic base is preferably present in an amount
in the range of from about 1.5 to about 3.0 molar equivalents (relative
to the moles of the compound of formula (X-S)), more preferably in an
amount of about 2.5 molar equivalents;

[0261] in an organic solvent such as DMA, DMF, NMP, acetonitrile, and the
like, or mixture thereof, preferably DMA or a mixture of DMA and
acetonitrile; preferably at a temperature in the range of from about
75° C. to about reflux temperature, more preferably at a
temperature in the range of form about 90° C. to about 125°
C.; to yield the corresponding compound (I-B).

[0262] Preferably compound (I-B) is further reacted with a suitably
selected acid such as HCl; in an organic solvent or mixture of organic
solvents, such as IPA or a mixture of IPA and ethylmethylketone; to yield
the corresponding salt of compound (I-B).

[0263] In another embodiment, the present invention is directed to
processes for the preparation of compound (I-C), as outlined in more
detail in Scheme 7, below.

##STR00038##

[0264] Accordingly, a suitably substituted compound of formula (X-S),
prepared as described herein, is reacted with a compound of formula
(XIII-C), a known compound or compound prepared by known methods; wherein
the compound of formula (XIII-C) is preferably present in an amount in
the range of from about 1.0 to about 3.0 molar equivalents (relative to
the moles of the compound of formula (X-S)), more preferably in an amount
in the range of from about 1.1 to about 1.5 molar equivalents, more
preferably, in an amount of about 1.2 molar equivalents;

[0265] in the presence of a suitably selected second inorganic base such
as KOH, KO-t-Bu, NaOH, NaO-t-Bu, and the like, preferably KOH; wherein
the inorganic base is preferably present in an amount in the range of
from 1.0 to about 5.0 molar equivalents (relative to the moles of the
compound of formula (X-S)), more preferably in an amount in the range of
from about 2.0 to about 4.0 molar equivalents, more preferably, in an
amount of about 3.3 molar equivalents;

[0266] optionally in the presence of a suitably selected additive such as
a suitably selected crown ether such as 18-crown-6, or a suitably
selected additive such as diglyme, and the like; wherein the additive is
preferably present in a catalytic amount;

[0267] in an organic solvent such as toluene, THF, 2-methyl-THF, and the
like, or a mixture of organic solvent and water, preferably toluene;
preferably at a temperature in the range of from 60° C. to about
reflux temperature, more preferably at about reflux temperature; to yield
the corresponding compound (I-C).

[0268] Alternatively, a suitably substituted compound of formula (X-S),
present as its corresponding pharmaceutically acceptable salt, preferably
as its corresponding HCl salt, prepared as for example described herein,
is reacted with a suitably selected first inorganic base such as sodium
carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide,
sodium bicarbonate, potassium bicarbonate, and the like, preferably
sodium carbonate; wherein the base is present in an amount in the range
of from about 1.0 to about 2.0 molar equivalents (relative to the moles
of the compound of formula (X-S), more preferably, in an amount of about
1.5 molar equivalents; to liberate the free base of the compound of
formula (X-S)); wherein the resulting salt is preferably removed from the
resulting biphasic mixture in the aqueous layer;

[0269] the liberated free base of the compound of formula (X-S) is then
reacted with a compound of formula (XIII-C), a known compound or compound
prepared by known methods; wherein the compound of formula (XIII-C) is
preferably present in an amount in the range of from about 1.0 to about
3.0 molar equivalents (relative to the moles of the compound of formula
(X-S)), more preferably in an amount of about 1.2 molar equivalents;

[0270] in the presence of a suitably selected second inorganic base such
as KOH, KO-t-Bu, NaOH, NaO-t-Bu, and the like, preferably KOH; wherein
the inorganic base is preferably present in an amount in the range of
from 1.0 to about 5.0 molar equivalents (relative to the moles of the
compound of formula (X-S)), more preferably in an amount in the range of
from about 2.0 to about 4.0 molar equivalents, more preferably, in an
amount of about 3.3 equivalents;

[0271] optionally in the presence of a suitably selected additive such as
a suitably selected crown ether such as 18-crown-6 (also known as
1,4,7,10,13,16-hexaoxacyclooctadecane), or a suitably selected additive
such as diglyme (also known as bis(2-methoxyethyl)ether), and the like;
wherein the additive is preferably present in a catalytic amount;

[0272] in an organic solvent such as toluene, THF, 2-methyl-THF, and the
like, or a mixture of organic solvent and water, preferably toluene;
preferably at a temperature in the range of from 60° C. to about
reflux temperature, more preferably at about reflux temperature; to yield
the corresponding compound (I-C).

[0273] Preferably compound (I-C) is further reacted with a suitably
selected acid such as anhydrous HCl; in an organic solvent such as IPA,
and the like; to yield the corresponding salt of compound (I-C).

[0274] The present invention is further directed to two novel crystalline
HCl salts of compound (I-B), more particularly FORM I and FORM II. A
representative powder X-ray diffraction (XRD) spectra of the crystalline
HCl salt of compound (I-B) FORM I is shown in FIG. 1. A representative
powder X-ray diffraction (XRD) spectra of the crystalline HCl salt of
compound (I-B) FORM II is shown in FIG. 2. The present invention is
further directed to a novel crystalline HCl salt of compound (I-C). A
representative powder XRD spectra of the crystalline HCl salt of compound
(I-C) is shown in FIG. 3.

[0275] The powder XRD spectrum of a representative sample of the
crystalline HCl salt of compound (I-B) FORM I and a representative sample
of the crystalline HCl salt of compound (I-C) was measured using an
XPERT-PRO diffractometer system. The sample was back-loaded into a
conventional x-ray holder, at 25° C. The sample was scanned from 4
to 41° 2θ with a step size of 0.0170° 2θ and a
time per step of 17.44 seconds. Instrument voltage and current settings
were 45 kV and 40 mA.

[0276] The powder XRD spectrum of a representative sample of the
crystalline HCl salt of compound (I-B) FORM II was measured using a
computer controlled powder diffractometer system (APD2000 by G. N. R. s.
r. I.). The sample was back-loaded into an X-ray holder for automatic
sample changer, at 25° C. The sample was scanned from 3 to
40° 2θ with a step size of 0.01° 2θ and a time
per step of 5 seconds. Instrument voltage and current settings were 40 kV
and 30 mA.

[0277] The crystalline HCl salt of compound (I-B) FORM I, may be
characterized by its X-ray diffraction pattern, comprising the peaks as
listed in Table 1, below.

[0278] Preferably, the crystalline HCl salt of compound (I-B), FORM I is
characterized by its powder XRD pattern, which comprises peaks having a
relative intensity greater than or equal to about 20%, as listed in Table
2 below.

[0279] More preferably, the crystalline HCl salt of compound (I-B), FORM I
is characterized by its powder XRD pattern, which comprises peaks having
a relative intensity greater than or equal to about 25%, more preferably
greater than or equal to about 50%.

[0280] The crystalline HCl salt of compound (I-B) FORM II, may be
characterized by its X-ray diffraction pattern, comprising the peaks as
listed in Table 3, below.

[0281] Preferably, the crystalline HCl salt of compound (I-B), FORM II is
characterized by its powder XRD pattern, which comprises peaks having a
relative intensity greater than or equal to about 25%, as listed in Table
4 below.

[0282] More preferably, the crystalline HCl salt of compound (I-B), FORM
II is characterized by its powder XRD pattern, which comprises peaks
having a relative intensity greater than or equal to about 50%.

[0283] The crystalline HCl salt of compound (I-C), may be characterized by
its X-ray diffraction pattern, comprising the peaks as listed in Table 5,
below.

[0284] Preferably, the crystalline HCl salt of compound (I-C) is
characterized by its powder XRD pattern, which comprises peaks having a
relative intensity greater than or equal to about 20%, as listed in Table
6 below.

[0285] More preferably, the crystalline HCl salt of compound (I-C) is
characterized by its powder XRD pattern, which comprises peaks having a
relative intensity greater than or equal to about 25%, more preferably
greater than or equal to about 50%.

[0286] The present invention further comprises pharmaceutical compositions
containing one or more compounds prepared according to any of the
processes described herein with a pharmaceutically acceptable carrier.
Pharmaceutical compositions containing one or more of the compounds of
the invention described herein as the active ingredient can be prepared
by intimately mixing the compound or compounds with a pharmaceutical
carrier according to conventional pharmaceutical compounding techniques.
The carrier may take a wide variety of forms depending upon the desired
route of administration (e.g., oral, parenteral). Thus for liquid oral
preparations such as suspensions, elixirs and solutions, suitable
carriers and additives include water, glycols, oils, alcohols, flavoring
agents, preservatives, stabilizers, coloring agents and the like; for
solid oral preparations, such as powders, capsules and tablets, suitable
carriers and additives include starches, sugars, diluents, granulating
agents, lubricants, binders, disintegrating agents and the like. Solid
oral preparations may also be coated with substances such as sugars or be
enteric-coated so as to modulate major site of absorption. For parenteral
administration, the carrier will usually consist of sterile water and
other ingredients may be added to increase solubility or preservation.
Injectable suspensions or solutions may also be prepared utilizing
aqueous carriers along with appropriate additives.

[0287] To prepare the pharmaceutical compositions of this invention, one
or more compounds of the present invention as the active ingredient is
intimately admixed with a pharmaceutical carrier according to
conventional pharmaceutical compounding techniques, which carrier may
take a wide variety of forms depending of the form of preparation desired
for administration, e.g., oral or parenteral such as intramuscular. In
preparing the compositions in oral dosage form, any of the usual
pharmaceutical media may be employed. Thus, for liquid oral preparations,
such as for example, suspensions, elixirs and solutions, suitable
carriers and additives include water, glycols, oils, alcohols, flavoring
agents, preservatives, coloring agents and the like; for solid oral
preparations such as, for example, powders, capsules, caplets, gelcaps
and tablets, suitable carriers and additives include starches, sugars,
diluents, granulating agents, lubricants, binders, disintegrating agents
and the like. Because of their ease in administration, tablets and
capsules represent the most advantageous oral dosage unit form, in which
case solid pharmaceutical carriers are obviously employed. If desired,
tablets may be sugar coated or enteric coated by standard techniques. For
parenterals, the carrier will usually comprise sterile water, through
other ingredients, for example, for purposes such as aiding solubility or
for preservation, may be included. Injectable suspensions may also be
prepared, in which case appropriate liquid carriers, suspending agents
and the like may be employed. The pharmaceutical compositions herein will
contain, per dosage unit, e.g., tablet, capsule, powder, injection,
teaspoonful and the like, an amount of the active ingredient necessary to
deliver an effective dose as described above. The pharmaceutical
compositions herein will contain, per unit dosage unit, e.g., tablet,
capsule, powder, injection, suppository, teaspoonful and the like, of
from about 0.001-1,000 mg or any range therein, and may be given at a
dosage of from about 0.01-100 mg/kg/day, or any range therein, preferably
from about 0.01-50 mg/kg/day, or any range therein, more preferably from
about 0.01-10 mg/kg/day, or any range therein, more preferably from about
0.05-1 mg/kg/day, or any range therein. The dosages, however, may be
varied depending upon the requirement of the patients, the severity of
the condition being treated and the compound being employed. The use of
either daily administration or post-periodic dosing may be employed.

[0288] Preferably these compositions are in unit dosage forms from such as
tablets, pills, capsules, powders, granules, sterile parenteral solutions
or suspensions, metered aerosol or liquid sprays, drops, ampoules,
autoinjector devices or suppositories; for oral parenteral, intranasal,
sublingual or rectal administration, or for administration by inhalation
or insufflation. Alternatively, the composition may be presented in a
form suitable for once-weekly or once-monthly administration; for
example, an insoluble salt of the active compound, such as the decanoate
salt, may be adapted to provide a depot preparation for intramuscular
injection. For preparing solid compositions such as tablets, the
principal active ingredient is mixed with a pharmaceutical carrier, e.g.
conventional tableting ingredients such as corn starch, lactose, sucrose,
sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or
gums, and other pharmaceutical diluents, e.g. water, to form a solid
preformulation composition containing a homogeneous mixture of a compound
of the present invention, or a pharmaceutically acceptable salt thereof.
When referring to these preformulation compositions as homogeneous, it is
meant that the active ingredient is dispersed evenly throughout the
composition so that the composition may be readily subdivided into
equally effective dosage forms such as tablets, pills and capsules. This
solid preformulation composition is then subdivided into unit dosage
forms of the type described above containing from 0.001 to about 1000 mg,
or any range therein, for example at 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50
mg, 75 mg, 100 mg, or any amount therein, of the active ingredient of the
present invention. The tablets or pills of the novel composition can be
coated or otherwise compounded to provide a dosage form affording the
advantage of prolonged action. For example, the tablet or pill can
comprise an inner dosage and an outer dosage component, the latter being
in the form of an envelope over the former. The two components can be
separated by an enteric layer which serves to resist disintegration in
the stomach and permits the inner component to pass intact into the
duodenum or to be delayed in release. A variety of material can be used
for such enteric layers or coatings, such materials including a number of
polymeric acids with such materials as shellac, cetyl alcohol and
cellulose acetate.

[0289] The liquid forms in which the novel compositions of the present
invention may be incorporated for administration orally or by injection
include, aqueous solutions, suitably flavored syrups, aqueous or oil
suspensions, and flavoured emulsions with edible oils such as cottonseed
oil, sesame oil, coconut oil or peanut oil, as well as elixirs and
similar pharmaceutical vehicles. Suitable dispersing or suspending agents
for aqueous suspensions, include synthetic and natural gums such as
tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,
methylcellulose, polyvinyl-pyrrolidone or gelatin.

[0290] The method of treating described in the present invention may also
be carried out using a pharmaceutical composition comprising any of the
compounds as defined herein and a pharmaceutically acceptable carrier.
The pharmaceutical composition may contain between about 0.001 mg and
1000 mg of the compound, or any range therein; preferably about 0.01 to
10 mg of the compound, or any range therein, more preferably about 0.01
to 1 mg of the compound, or any range therein, more preferably about 0.01
to about 0.05 mg, or any range thereof, and may be constituted into any
form suitable for the mode of administration selected. Carriers include
necessary and inert pharmaceutical excipients, including, but not limited
to, binders, suspending agents, lubricants, flavourants, sweeteners,
preservatives, dyes, and coatings. Compositions suitable for oral
administration include solid forms, such as pills, tablets, caplets,
capsules (each including immediate release, timed release and sustained
release formulations), granules, and powders, and liquid forms, such as
solutions, syrups, elixirs, emulsions, and suspensions. Forms useful for
parenteral administration include sterile solutions, emulsions and
suspensions.

[0291] Advantageously, compounds of the present invention may be
administered in a single daily dose, or the total daily dosage may be
administered in divided doses of two, three or four times daily.
Furthermore, compounds for the present invention can be administered in
intranasal form via topical use of suitable intranasal vehicles, or via
transdermal skin patches well known to those of ordinary skill in that
art. To be administered in the form of a transdermal delivery system, the
dosage administration will, of course, be continuous rather than
intermittent throughout the dosage regimen.

[0292] For instance, for oral administration in the form of a tablet or
capsule, the active drug component can be combined with an oral,
non-toxic pharmaceutically acceptable inert carrier such as ethanol,
glycerol, water and the like. Moreover, when desired or necessary,
suitable binders; lubricants, disintegrating agents and coloring agents
can also be incorporated into the mixture. Suitable binders include,
without limitation, starch, gelatin, natural sugars such as glucose or
beta-lactose, corn sweeteners, natural and synthetic gums such as acacia,
tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium
benzoate, sodium acetate, sodium chloride and the like. Disintegrators
include, without limitation, starch, methylcellulose, agar, bentonite,
xanthan gum and the like.

[0293] The liquid forms in suitably flavored suspending or dispersing
agents such as the synthetic and natural gums, for example, tragacanth,
acacia, methyl-cellulose and the like. For parenteral administration,
sterile suspensions and solutions are desired. Isotonic preparations
which generally contain suitable preservatives are employed when
intravenous administration is desired.

[0294] To prepare a pharmaceutical composition of the present invention, a
compound of formula (I) as the active ingredient is intimately admixed
with a pharmaceutical carrier according to conventional pharmaceutical
compounding techniques, which carrier may take a wide variety of forms
depending of the form of preparation desired for administration (e.g.
oral or parenteral). Suitable pharmaceutically acceptable carriers are
well known in the art. Descriptions of some of these pharmaceutically
acceptable carriers may be found in The Handbook of Pharmaceutical
Excipients, published by the American Pharmaceutical Association and the
Pharmaceutical Society of Great Britain.

[0296] Compounds of this invention may be administered in any of the
foregoing compositions and according to dosage regimens established in
the art whenever treatment of diseases, disorders or conditions modulated
by the histamine H3 receptor is required.

[0297] The daily dosage of the products may be varied over a wide range
from 0.001 to 1,000 mg per adult human per day, or any range therein. For
oral administration, the compositions are preferably provided in the form
of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0,
25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active
ingredient for the symptomatic adjustment of the dosage to the patient to
be treated. An effective amount of the drug is ordinarily supplied at a
dosage level of from about 0.01 mg/kg to about 100 mg/kg of body weight
per day, or any range therein. Preferably, the range is from about 0.01
to about 50.0 mg/kg of body weight per day, or any range therein. More
preferably, from about 0.01 to about 10.0 mg/kg of body weight per day,
or any range therein. More preferably, from about 0.01 to about 1.0 mg/kg
of body weight per day, or any range therein. The compounds may be
administered on a regimen of 1 to 4 times per day.

[0298] Optimal dosages to be administered may be readily determined by
those skilled in the art, and will vary with the particular compound
used, the mode of administration, the strength of the preparation, the
mode of administration, and the advancement of the disease condition. In
addition, factors associated with the particular patient being treated,
including patient age, weight, diet and time of administration, will
result in the need to adjust dosages.

[0299] One skilled in the art will recognize that, both in vivo and in
vitro trials using suitable, known and generally accepted cell and/or
animal models are predictive of the ability of a test compound to treat
or prevent a given disorder.

[0300] One skilled in the art will further recognize that human clinical
trials including first-in-human, dose ranging and efficacy trials, in
healthy patients and/or those suffering from a given disorder, may be
completed according to methods well known in the clinical and medical
arts.

[0301] The following Examples are set forth to aid in the understanding of
the invention, and are not intended and should not be construed to limit
in any way the invention set forth in the claims which follow thereafter.

[0302] In the Examples which follow, some synthesis products are listed as
having been isolated as a residue. It will be understood by one of
ordinary skill in the art that the term "residue" does not limit the
physical state in which the product was isolated and may include, for
example, a solid, an oil, a foam, a gum, a syrup, and the like.

Example 1

(6-Chloro-pyridin-3-yl)-[1,4]diazepan-1-yl-methanone

##STR00039##

[0304] A solution of homopiperazine (385.62 g, 3.85 mol) in THF (3.9 L)
was cooled to an internal temperature of 0° C. and ethyl
6-chloronicotinate (285.82 g, 1.54 mol) was added in THF (0.57 L) over 5
min. After stirring for 10 minutes, n-hexyl lithium (2.3 M in hexane, 335
mL, 0.77 mol) was added to the resulting mixture, over 40 min. The
resulting mixture was stirred for 2 h at 0° C., then warmed to
20° C. over 1 h. After an additional 15 h at 20° C., the
resulting mixture was treated with 1M NaOAc/HOAc buffer (5 L) (prepared
by diluting 47.35 g of sodium acetate and 253.2 mL of acetic acid with
water to a total volume of 5 L).

[0305] The resulting layers were separated and the aqueous layer pH was
then increased from 8.0 to 11.35 with 50% NaOH.sub.(aq) solution (153
mL). The basic layer was extracted with dichloromethane (2×4 L) and
the resulting organics dried with sodium sulfate, filtered, and
concentrated to yield a thick oil.

[0309] A solution of homopiperazine (12.5 g, 125 mmol) and
ethyl-6-chloronicotinate (9.28 g, 50 mmol) in THF (150 mL) was cooled to
0° C. and LiOEt (1 M in THF, 50 mL, 50 mmol) was then added over
20 minutes. The resulting mixture was stirred at 0° C. for 2 h,
then warmed to 20° C. and held at this temperature for 17 h. The
resulting mixture was then treated with 162 mL of an aqueous solution
containing 1.53 g of NaOAc and 8.2 mL of acetic acid. The resulting
layers were separated and the organic was diluted with hexane (50 mL) and
extracted again with the same aqueous solution as utilized above. The
aqueous pH was then increased to 10 through addition of 50% NaOH.sub.(aq)
(15 mL). After extraction with dichloromethane (3×250 mL) the
combined organics were dried over sodium sulfate, filtered, and
concentrated to yield the title compound as an oil.

Example 3

(6-Chloro-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone

##STR00041##

[0311] To a solution of
(6-chloro-pyridin-3-yl)[1,4]diazepan-1-yl-methanone (255.1 g, 1.06 mol)
in dichloroethane (3.0 L) was added cyclobutanone (108.1 mL, 1.45 mol).
After a 1 h aging period, sodium triacetoxyborohydride (308.2 g, 1.45
mol) was added in four equal portions over 1.5 h. The resulting mixture
was allowed to stir for 20 h, then quenched with 2.5 L of an aqueous
solution containing NaOH (141.3 g, 3.53 mol). After stirring for 30
minutes, the layers were separated and the organic dried with magnesium
sulfate, filtered, and concentrated to yield the title compound as an
oil.

Example 4

Purification of
(6-Chloro-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone

[0312] The oil prepared as in Example 4 above was purified through
formation of the corresponding tartrate salt as follows.

[0313] To the
(6-chloro-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepam-1-yl)-methanone
(311.5 g actual desired, 1.06 mol) oil in ethanol (3.0 L) was added
L-tartaric acid (167.05 g, 1.11 mol). The resulting heterogeneous
suspension was warmed to 80° C. over 45 minutes and held for 1 h.
The resulting mixture was then cooled to 20° C. over 3 h and
stirred at 20° C. for 1 h. The resulting solids were filtered and
washed with ethanol (1 L). The resulting material was dried under vacuum
at 43° C. to yield an off-white solid, the corresponding tartaric
acid salt or
(6-chloro-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepam-1-yl)-methanone.

[0314] A portion of the tartrate salt was then reacted to yield the
(6-chloro-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepam-1-yl)-methanone free
base as follows.

[0315] A mixture of
(6-chloro-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone-L-tar-
taric acid (172 g, 386.9 mmol), iPrOAc (1.5 L), and 1 N NaOH.sub.(aq) (1.5
L) was thoroughly mixed and the resulting layers were separated. The
aqueous layer was extracted with additional iPrOAc (1.5 L) and the
combined organic layers were dried over magnesium sulfate. After
filtration and concentration,
(6-chloro-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepam-1-yl)-methanone was
obtained as a yellow oil.

[0319] To a solution of
(6-chloro-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone
(101.0 g, 343.8 mmol) in dimethylacetamide (1.1 L) was added
Cs2CO3 (224 g, 687.6 mmol) and m-cyanophenol (81.9 g, 687.6
mmol). The resulting mixture was warmed to 125° C. and stirred for
20 h. After cooling to room temperature, the resulting mixture was
filtered and acetic acid (1.5 L) was added to the filtrate. The resulting
mixture was concentrated under reduced pressure to yield a brown residue
which was taken up into MTBE (1.5 L) and 1N NaOH.sub.(aq) (1.5 L). The
resulting layers were thoroughly mixed and then separated. The organic
extract was dried over magnesium sulfate, filtered, and concentrated to
yield the title compound as a brown oil.

[0323] A slurry of
3-[5-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-pyridin-2-yloxy]-benzonitri-
le (10.4 g, 27.6 mmol) in isopropanol (80 mL) was warmed to 50° C.
To the resulting solution was added anhydrous HCl (5.54 mL, 5 M HCl in
IPA, 27.7 mmol). The resulting mixture was cooled to 20° C. over 1
h, and then held at 20° C. for 20 h. The resulting slurry was
filtered, washed with isopropanol, and dried at 50° C. in a vacuum
oven to yield the title compound as an off-white crystalline solid.

[0325] A solution of
3-[5-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-pyridin-2-yloxy]-benzonitri-
le (114 g, 302.8 mmol) in IPA (900 mL) was warmed to 40° C. To the
resulting solution was added anhydrous HCl (5-6 M solution in IPA, 60.6
mL, 302.8 mmol). After the addition of seed crystals (which may be
prepared for example, as described in Example 6 above), the resulting
mixture was cooled to 35° C. and held for two hours. The resulting
mixture was cooled to room temperature, filtered, washed with IPA (220
mL), and the isolated residue dried at 50° C. to yield the title
compound as an off-white crystalline solid.

[0328] To a solution of
(6-chloro-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone (32.7
g, 111.3 mmol) in toluene (470 mL) was added tetrahydro-pyran-4-ol (13.6
g, 133.6 mmol), 18-crown-6 (1.47 g, 5.565 mmol), and then KOH (pulverized
solid, 20.6 g, 367.3 mmol). The resulting heterogeneous mixture was
warmed to 110° C. and stirred for 3 h. After cooling to room
temperature, water (470 mL) was added and the resulting layers were
thoroughly mixed and then separated. The organic extract was dried over
magnesium sulfate, filtered, and concentrated to yield the title compound
as a yellow oil.

[0332] To a solution of
(4-cyclobutyl-[1,4]diazepam-1-yl)-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-
-yl]-methanone (200 mg, 0.56 mmol) in isopropanol (1.5 mL) was added
anhydrous HCl (112 μL, 5 M HCl in IPA, 0.56 mmoL). The resulting
slurry was warmed to 80° C. and then cooled to 45° C. and
stirred overnight. After further cooling to room temperature, the title
compound was isolated as a white crystalline solid.

[0334] To a solution of
(4-cyclobutyl-[1,4]diazepan-1-yl)-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-
-yl]-methanone (6.17 g, 17.2 mmol) in IPA (100 mL) was added anhydrous HCl
(5-6 M solution in IPA, 3.44 mL, 17.2 mmol). The resulting mixture was
then warmed to 80° C. and then cooled to 60° C. to promote
precipitation. Seed crystals (which may be prepared for example, as
described in Example 9 above) were added at this point. The resulting
mixture was cooled to room temperature, filtered, washed with IPA (50
mL), and dried at 50° C. to yield the title compound as its
corresponding HCl salt, as a white crystalline solid.

[0338] A mixture of
(6-chloro-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone (308
mg, 1.05 mmol), cesium carbonate (683 mg, 2.1 mmol), 4-fluorophenol (235
mg, 2.1 mmol), and N,N-dimethylacetamide (5 mL) was heated at 110°
C. for 15 h. The resulting mixture was then cooled, filtered, and diluted
with acetic acid (10 mL). The resulting solution was concentrated under
reduced pressure and then partitioned between MTBE (10 mL) and 1N
NaOH.sub.(aq) (10 mL). The organic layer was diluted with
dichloromethane, washed with water and concentrated to yield the title
compound as a yellow oil.

[0341] Under a nitrogen atmosphere, homopiperazine (also known as
[1,4]-diazepane, 30.05 g, 0.3 mol, 1 eq) was dissolved in toluene (150
g). To the resulting solution was added cyclobutanone (21.03 g, 0.3 mol,
1 eq). The resulting mixture was heated to ˜80-87° C., 1000
mbar for 2 hours and then at ˜90-125° C., 800 mbar for 2
hours. The water formed as a result of the reaction removed by means of a
Dean-Stark apparatus (˜5.4 g). The residual solvent was then
distilled off to yield a residue, the title compound as an orange oil.
The oil was used in subsequent steps without further purification.

Example 13

1-Cyclobutyl-[1,4]diazepane

##STR00050##

[0343] Under a nitrogen atmosphere, 32% aqueous hydrochloric acid (227.9
g, 2 mol, 4 eq) was cooled to a temperature in the range of -5° C.
to 0° C. Homopiperazine-cyclobutylaminal prepared as in Example 12
above (89.6 g, 0.5 mol), was added dropwise while maintaining the
internal temperature of the reaction mixture at -5° C. to
0° C. (about 1-2 hours). To the resulting mixture was then added a
solution of sodium borohydride (18.9 g, 0.5 mol, 1 eq) in water (37.5 g)
stabilized with sodium hydroxide (6.7 g, 30% NaOH.sub.(aq), 0.05 mol, 0.1
eq) while maintaining the temperature of the reaction mixture at
-2° C. to 2° C. (about 2-3 hours). After the addition, the
resulting mixture was warmed to 20-25° C. and stirred overnight.
The resulting mixture was then neutralized with 30% sodium hydroxide
(273.4 g, 2.05 mol, 2.01 eq) and then extracted with MTBE (3×111
g). The organic layers were combined, the resulting suspension was
filtered and the flask and filter cake washed with MTBE (14.8 g). Any
remaining residual solvent was removed to yield the title compound as a
yellowish oil, which was used in subsequent steps without further
purification.

[0345] 6-Chloronicotinic acid chloride (25.0 g, 137.8 mmol, 1 eq) was
dissolved in 2-methyl-THF (328.0 g). A solution of
1-cyclobutyl-[1,4]diazepane (prepared as in Example 13 above, 24.1 g,
147.8 mmol, 1.05 eq) in 2-methyl-THF (164.0 g) was then added to the
reaction mixture, while maintaining the temperature of the reaction
mixture at less than 35° C. (about 45 min-1.5 hours). The
resulting suspension was stirred at room temperature for 16 hours, then
cooled to about 0-5° C. and maintained at 0° C. for 2
hours. The title compound was isolated by filtration, washed with
2-methyl-THF (2×45.0 g), then dried in vacuo at 60° C., to
yield the title compound as a white solid.

[0347] To a suspension of 95% sodium triacetoxyborohydride (4.34 g, 19.45
mmol) in THF (30.0 g) was added a solution of
homopiperazine-cyclobutylaminal (2.70 g, 17.74 mmol) in THF (5.4 g) at
about 20-25° C. and the resulting mixture stirred for 1 hour. To
the resulting mixture was then added 97% 6-chloronicotinic acid chloride
(3.0 g, 16.53 mmol) in THF (12.0 g) and the resulting mixture stirred at
room temperature for 1 hour. Excess sodium triacetoxyborohydride was then
quenched with water (5.0 g). After stirring 15 minutes, 10% NaOH.sub.(aq)
(16.5 g) was added and the mixture stirred for 25 minutes. The resulting
layers were separated, the organic layer washed with brine (10.5 g). The
organic layer was again separated and filtered. To the organic layer was
then added toluene (16.2 g), part of the solvent distilled off at 220
mbar, 45° C. At 38° C., 6N HCl in isopropanol was added
dropwise, resulting in the formation of two layers. Additional
isopropanol was added (2.6 g). The solvent was then completely removed to
yield a yellowish foam residue. The residue was dissolved in ethanol
(12.0 g) and MTBE (50 g) added, resulting in the formation of a
precipitate. The resulting mixture was heated to 50° C., cooled
slowly to room temperature and stirred overnight. The title compound was
isolated by filtration, washed with MTBE (2×20 g, 1×10 g) and
dried in vacuo at 45° C. to yield a white solid.

[0349] (6-Chloro-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone
(20.0 g, 51 mmol), sodium carbonate (8.0 g, 75.5 mmol), water (72.0 g)
and toluene (100.0 g) were mixed for 30 minutes at room temperature. The
resulting biphasic mixture was separated and the aqueous layer removed.
The remaining organic layer was concentrated in vacuo to yield a yellow
oil (14.97 g). Tetrahydropyran-4-ol (6.24 g, 61.1 mmol), potassium
hydroxide (4.75 g, 84.7 mmol) and toluene (200 g) were added, the
resulting mixture heated to reflux and the water formed in the reaction
removed with a Dean-Stark apparatus. The resulting mixture was cooled to
20-30° C. and water (80.0 g) was added. The resulting mixture was
stirred for 10 min, the layers allowed to separate and the aqueous layer
removed. The organic layer was slightly concentrated to remove any traces
of water, then treated with a mixture of 6N HCl in isopropanol (10.98 g,
61.2 mmol) and toluene (70 g) at 60-70° C. The resulting
suspension was maintained at 60° C. for 1 hour, then cooled to
0-5° C. over about 3 hours, then maintained at 0° C. for 30
min. The precipitate was isolated by filtration, washed with toluene
(2×10 g) and dried in vacuo to yield the title compound as a white
solid.

[0350] Recrystallization: The white solid prepared above (13.5 g, 34.1
mmol) was dissolved in isopropanol (265.0 g) at reflux. The resulting
mixture was cooled to 55-65° C. over about 40 min, during which
time crystallization slowly set in. The resulting mixture was maintained
at 55-65° C. for 2 hours, then cooled to room temperature and held
overnight. The resulting mixture was re-heated to 45° C., and held
at this temperature for 2.5 hours. The resulting suspension was then
cooled to 0-5° C. over about 1.5 hours and then held at this
temperature for 1 hour. The title compound was isolated by filtration,
washed with isopropanol (2×15 g), dried in vacuo at 75-100°
C. to yield a white solid.

[0352] A reactor was charged with
(6-chloro-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepam-1-yl-methanone
hydrochloride (20.0 g, 60.6 mmol), 3-hydroxybenzonitrile (10.8 g, 90.7
mmol), cesium carbonate (52.5 g, 151.6 mmol), acetonitrile (62.6 g) and
dimethylacetamide (50.0 g). The resulting yellowish suspension was heated
to reflux (95° C.) over about 15 min and maintained at reflux for
65 min. The acetonitrile was then distilled off, until the temperature
had risen to about 105-110° C. The resulting mixture was then
stirred at 105-110° C. for 5 hours, then cooled to 20° C.
and held at this temperature overnight. The resulting mixture was then
re-heated to reflux for another 4 hours, 15 min, then cooled to
65° C., the cesium salts were removed by filtration and the filter
cake washed with acetonitrile (20.5 g) via the reactor. To the filtrate
was added water (60.1 g), then acetonitrile was removed by distillation
in vacuo (50-55° C., 250-70 mbar). The resulting residue was
extracted twice with MTBE (65.0 g, respectively) at 45° C. The
combined organic layers were washed with 2 N NaH.sub.(aq) (20 g) and
water (2×20 g) at 45° C. Approximately 50% of the solvent
was then distilled off from the organic layer and some seed crystals of
the desired product crystalline form were added. The resulting mixture
was then cooled to room temperature over about 2.5 hours, and held at
this temperature overnight. The resulting mixture was heated to
35° C., and cyclohexane (100.0 g) was added over about 1.5 hours.
The resulting, thick, slightly pink suspension was held at 35° C.
for 1 hour, then cooled to 15° C. over about 2 h, held at
15° C. for 2 hours, cooled to 0° C. over about 1 hour and
held at 0° C. for 1 hour, 10 min. The title compound was isolated
by filtration, washed with cyclohexane and dried in vacuo at 50°
C. to yield an off-white solid.

[0354] 3-[5-(4-Cyclobutyl-[1,4]diazepane-1-carbonyl)-pyridin-2-yloxy]-benz-
onitrile (prepared as described in Example 17 above, 14.0 g, 37.2 mmol)
was dissolved in ethylmethylketone (112.0 g) and isopropanol (7.0 g) at
room temperature. The resulting solution was filtered (absolute
filtration), the reactor and filter washed with ethylmethylketone (28.0
g). The resulting solution was then heated to 55-60° C., HCl 37%
aq. (2.10 g, 21.3 mmol) was added dropwise over 15 min, and then after 5
min some seeding crystals (0.05 g) of the desired crystalline form were
added. The resulting mixture was held at 55-57° C. for 38 min, and
then HCl 37% aq. (2.10 g, 21.3 mmol) was added dropwise over 30 min. The
resulting white suspension was held at 55-60° C. for 1 hour, 20
min, then cooled to 25° C. over about 3 hours and held at this
temperature overnight. The resulting mixture was then cooled to
0-5° C. and held at this temperature for 1.5 hours. The title
compound was isolated by filtration, washed with ethylmethylketone
(2×28 g) and dried in vacuo at 80° C. to yield a white,
crystalline solid.

[0356] A suspension of
(6-chloro-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepam-1-yl-methanone
hydrochloride (2.0 g, 5.83 mmol), 4-fluorophenol (1.0 g, 8.92 mmol) and
cesium carbonate (5.8 g, 17.8 mmol) in dimethylacetamide (15.0 g) was
stirred at 100-110° C. After 4.5 hours, the cesium salts were
removed by filtration and the filter cake was washed with
t-butylmethylether (3×4.0 g). To the filtrate was added water (15.0
g) and the resulting mixture was stirred for 10 minutes at 40-45°
C. The resulting layers were separated, the aqueous layer was washed with
twice with t-butylmethylether (12.0 g and 6.0 g, respectively). The
organic layers were combined, then washed with 2 N NaOHaq (2.5 g)
and water (2×2.5 g). The organic layer was then concentrated (to
˜4.5 g) and toluene (10.0 g) added to the resulting residue. To the
resulting mixture, at 45° C., 6 N HCl in isopropanol (1.3 g, 7.84
mmol) was then added dropwise.

[0357] The title compound was observed to precipitate (at first forming as
an oil, with the beginning of crystallization after about 10 min). The
resulting mixture was stirred at 45° C. for 2 hours, then cooled
to 0° C. over about 5 hours, and held at 0° C. for 10
hours. The title compound was isolated by filtration, washed with toluene
and dried in vacuo at 55° C. to yield a white solid.

[0359] A mixture of 1-cyclobutyl-[1,4]diazepane (prepared e.g. as in
Example 13 above, 20.0 g, 129.7 mmol, 1.00 eq), water (95.2 g) and NaOH
30% aq. (34.6 g, 259.5 mmol, 2.00 eq) was cooled to 10-15° C. To
the resulting mixture was added a solution of 6-chloronicotinic acid
chloride (24.0 g, 136.4 mmol, 1.05 eq) in MTBE (250.0 g) at 10-15°
C., over about 30-45 min, while stirring vigorously. The resulting
emulsion was maintained at 10-20° C. for 45-60° C., before
the layers were allowed to separate. The aqueous layer was removed and
the organic layer washed with water (25.0 g). After removal of the
aqueous layer, the organic layer was concentrated by distillation (140 g
solvent are distilled off), ethanol (120 g) was added and additional
solvent was distilled off (170 g solvent). The resulting solution was
then heated to about 50-60° C. and HCl (gas, 4.8 g, 130.2 mmol) in
ethanol (9.1 g) was added dropwise. The resulting solution was cooled to
43-45° C. and seeded crystals of the title compound. The product
crystallized slowly at 43-45° C. when stirred for about 4-6 h.
MTBE (60 g over 1.5-2 h, 120 g over 0.5-1 h) was added, the resulting
mixture was then cooled to room temperature over 1-2 h and maintained for
1-2 h, before the title compound was isolated by filtration, washed with
MTBE (2×40 g) and dried in vacuo at 65-75° C. for 2 days, to
yield the title compound as a white solid.

[0361] 3-[5-(4-Cyclobutyl-[1,4]diazepane-1-carbonyl)-pyridin-2-yloxy]-benz-
onitrile.HCl (prepared e.g. as described in Example 18 above, 5.0 g, 12.1
mmol) was slurried in ethanol (15.0 g) at room temperature. The resulting
mixture was heated to reflux until the solid had completely dissolved. To
the resulting solution was then added 2-propanol (45.0 g) at 70°
C. After stirring at 80-85° C. for 20 min, the slightly turbid
solution was cooled to 55° C. over 15 minutes and seeding crystals
were added. The resulting mixture was kept at 55° C. for 15 min,
then it was cooled to 15° C. over 4 h and stirred overnight,
resulting in the formation of a thick white suspension. After cooling to
0° C. and stirring for 2 h, the title compound was isolated by
filtration, washed with 2-propanol (10 g) and dried in vacuo at 20 to
75° C. to yield a white, crystalline solid. (as FORM II)

Example 22

Oral Formulation (Prophetic Example)

[0362] As a specific embodiment of an oral composition, 100 mg of a
compound prepared as in Example 20 is formulated with sufficient finely
divided lactose to provide a total amount of 580 to 590 mg to fill a size
O hard gel capsule.

Example 23

Oral Formulation (Prophetic Example)

[0363] As a specific embodiment of an oral composition, 100 mg of a
compound prepared as in Example 16 is formulated with sufficient finely
divided lactose to provide a total amount of 580 to 590 mg to fill a size
O hard gel capsule.

Example 24

Oral Formulation (Prophetic Example)

[0364] As a specific embodiment of an oral composition, 100 mg of a
compound prepared as in Example 19 is formulated with sufficient finely
divided lactose to provide a total amount of 580 to 590 mg to fill a size
O hard gel capsule.

[0365] While the foregoing specification teaches the principles of the
present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the invention
encompasses all of the usual variations, adaptations and/or modifications
as come within the scope of the following claims and their equivalents.

Patent applications by Adrian Maurer, Schaffhausen CH

Patent applications by Daniel J. Pippel, Del Mar, CA US

Patent applications by Diego Broggini, Zurich CH

Patent applications by Lana K. Young, San Diego, CA US

Patent applications by Neelakandha S. Mani, San Diego, CA US

Patent applications by Vit Lellek, Zurich CH

Patent applications in class The nitrogens are in the 1,4-positions of the hetero ring

Patent applications in all subclasses The nitrogens are in the 1,4-positions of the hetero ring